Effect of Flow Rate and the Extracellular Fluid Volume on Proximal Urate and Water Absorption

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Kidney International, Vol. /7(1980), pp. 155 -16/

Effect of flow rate and the extracellular fluid volume on proximal urate and water absorption

HARRY 0. SENEKJIAN, THOMAS F. KNIGHT, STEVEN C. SANSOM, and EDWARD J. WEINMAN

Rena! Section, Department of Internal Medicine, Veterans Ad,ninist ration Medical Center and Baylor College of Medicine, Houston, Texas

Effect of flow rate and the extracellular fluid volume on proximal laboratory. It has been demonstrated previously urate and water absorption. The in vivo microperfusion tech- nique was used to examine the effect of variations in tubular flow that the state of hydration of the extracellular fluid rate and the extracellular fluid volume on [2-14C]-urate and water volume (ECV) affects urate transport [1—4]. Spe- absorption in the proximal tubule of the rat. In nondiuretic ani- cifically, expansion of the ECV with isotonic saline mals, fractional urate absorption was highest at the lowest perfusion rate examined and decreased as the rate of perfusion was resulted in an increase in urate excretion and an in- increased. Increasing the initial concentration of urate in the per- creased recovery of radioactive urate microinjected fusion solution had no effect on the fractional absorption of directly into the proximal tubule [1]. By analogy to urate. Fractional water absorption was also inversely related to the rate of perfusion. Expansion of the extracellular fluid volume the known changes in sodium reabsorption induced with isotonic saline resulted in rates of urate absorption similar by expansion of the ECV, we suggested a possible to control values at any given microperfusion rate. Fractional link between the reabsorption of sodium and that of water absorption showed the same flow rate dependency pattern observed in control animals, but at a significantly lower rate of urate. Other studies, however, indicated that the tu- absorption. These studies indicate that fractional urate absorp- bular absorption of sodium and water can be disso- tion is dependent upon some parameter of tubular flow rate and ciated from that of urate [5,6].We felt it important, that the relationship between urate absorption and perfusion rate is not related to the delivered load of urate per se and is not therefore, to reexamine the mechanism by which affected by the state of hydration of the extracellular fluid. alterations in the ECV affect urate transport. We also wished to examine the influence of flow rate on Effet du debit tubulaire et du volume des liquides extra-cellulaires sur Ia reabsorption proximale d'urate et d'eau. La microperfusion water reabsorption in the proximal convoluted in vivo a etC utilisée pour Ctudier l'effet des variations du debit tubule. tubulaire et du volume extra-cellulaire sur Ia reabsorption d'urate 2-'4C et d'eau dans le tube proximal du rat. Chez les ani- Methods maux non diurétiques, Ia reabsorption fractionnelle d'urate est Ia plus grande aux debits de perfusion les plus faibles utilisés et All studies were performed in male Sprague- diminue quand Ic debit de perfusion est augmentC. L'aug- Dawley rats anesthetized i.p. with pentobarbital so- mentation de Ia concentration initiale d'urate dans Ia solution perfusCe n'a pas d'effet sur Ia reabsorption fractionnelle. La dium (50mg/kgbody wt) and prepared for micro- reabsorption fractionnelle d'eau est aussi en fonction inverse du puncture as previously described [5].Eachanimal debit de perfusion. L'expansion du volume des liquides extra- received an infusion of isotonic saline equal to 1% cellulaires avec du chlorure de sodium isotonique a pour effet des debits de reabsorption d'urate semblables aux valeurs contrôles of body wt as replacement for surgical losses of a tous les debits de microperfusion. La reabsorption fraction- fluid. nelle d'eau reste dCpendante du debit de perfusion, comme chez Proximal tubule microperfusion studies were per- les animaux témoins, mais a des niveaux inférieurs de reabsorption. Ces résultats indiquent que Ia reabsorption fractionnelle formed with the Hampel microperfusion apparatus d'urate est dépendante d'un paramètre lie au debit tubulaire et as previously described [5].[2-'4C]-urate(specific que Ia relation entre Ia reabsorption d'urate et le debit de per- activity, 300tCiJrng)(Amersham Searle Corp., Ar- fusion n'est pas due au debit d'urate délivré et n'est pas modifiée par l'état d'hydratation du liquide extracellulaire. lington Heights, Illinois) was dissolved initially in a

Received for publication November 21, 1978 The determinants of the absorptive flux for urate and in revised form May 29, 1979 from the proximal tubule of the rat kidney have 0085-2538/80/0017—0155 $01.40 been under investigation in recent studies from this © 1980 by the International Society of Nephrology

155 156 Senekjian et a! solution containing sodium chloride (120 mEq/liter) Fractional water absorption (%/m,n tubule) =(I— and sodium bicarbonate (30 mEq/liter). An aliquot PF/CF1)x 100 X length of perfused tubule-' (2) of this solution was added to a 0.9-g/dl solution of sodium chloride containing [methoxy-3HJ-inulin Fractional urate absorption (%/mm tubule) =(1— (New England Nuclear Corp., Boston, Massachu- CFIPFurateICFIPF1n) x100 x length of perfused setts) to achieve a final urate concentration of 1.3 tubule (3) mg/dI. This concentration was confirmed by a un- case method with a glucose analyzer (Beckman In- The relationship between the fractional rates of struments Inc., Fullerton, California). The solution absorption of urate and water and the rate of per- was equilibrated with carbon dioxide, and the final fusion were represented by an exponential equation pH was 7.4. Where examined, unlabeled urate (final in the form: concentration of 10 mg/dl) or probenecid (2.8 mg/dl) was added to the perfusion solution. Following each Y =PIe2x microperfusion, the tubule was filled with a latex cast, and the distance between the perfusion and where e is the natural logarithm, x is the perfusion collecting sites was determined by microdissection rate, y is the fractional rate of absorption, and P1 after maceration of the kidney in hydrochloric acid. and P2 are coefficients that were estimated by the The effects of alterations in the perfusion rate on method of nonlinear least squares [7]. Statistical urate absorption were determined in 8 nondiuretic significance was determined using the Fisher test and 7 volume-expanded animals. The nondiuretic and Student's t test for unpaired data. rats received an i.v. infusion of saline at the rate of 1.2 mllhr throughout the study. Volume-expanded Results animals were infused with a volume of isotonic sa- The individual data points relating the fractional line equal to 10% of body wt over a 60-mm interval, absorption of urate and water, expressed as percent after which the infusion rate was adjusted to match per millimeter of perfused tubule length, to the mi- the urine flow rate. Isotonic saline containing 1.3 croperfusion rate in nondiuretic animals are sum- mgldl urate was used as the perfusion solution in marized in Table I and Fig. 1. As shown in Fig. 1, these studies. In 4 additional animals (2 nondiuretic fractional urate absorption was highest at the lowest animals and 2 volume-expanded animals), the mi- perfusion rates examined and decreased as the per- croperfusion solution was normal saline containing fusion rate was increased. The relationship between 1.3 mg/dl urate plus probenecid in a concentration the fractional rate of urate absorption and the per- of 2.8 mg/dl. In each group of studies, the rate of fusion rate is best described by the nonlinear regres- perfusion was altered by changing the speed of the sion equation y =29.7e_O0818x.Water absorption microperfusion pump. showed a marked perfusion rate dependency over a To examine the effect of increased urate concen- range of perfusion rates from 5 to 15 nllmin. At per- tration, we studied an additional 11 animals under fusion rates from 20 to 37 nI/mm, however, the frac- nondiuretic conditions. In these studies, the micro- tional rate of water absorption tended to decline on- perfusion solutions contained an initial concentra- ly slightly as a function of the perfusion rate. The tion of urate of either 1.3 or 10 mgldl. regression equation relating fractional water ab- Radioactivity of microperfusion solutions and sorption to the perfusion rate is y =4l.2e_o0432x. collected perfusate was measured in Biofluor (New To determine if the decrease in the fractional ab- England Nuclear) in a Tri-carb liquid scintillation sorption of urate with increasing rates of perfusion counter (Packard Instruments Co., Downers was a function of the perfusion rate itself or was a Grove, Illinois). Counts per minute were converted secondary consequence of the increased delivered to disintegrations per minute after corrections for load of urate, we performed additional studies with a quench, efficiency of counting, and crossover perfusion solution containing urate in an initial con- counts. For each microperfusion, the following cal- centration of 10 mg/dl. These results were com- culations were made: pared to a separate group of control observations that used a perfusion solution containing urate in a Perfusion rate (ni/mi,,) =CF/PF1x collected concentration of 1.3 mg/dl (Fig. 2). With the control volume X min' (I) solution, the relationship between fractional urate absorption and the rate of perfusion was y = where CF and PF are the disintegrations per minute 38.6e_O.0846xand was not significantly different from of [3H]-inulin in collected fluid (CF) and perfusion the values summarized in Fig. 1. With the perfusion fluid (PF), respectively. solution containing 10 mg/dl urate, the relationship F/ow rate and ECV effect on urate and F120 absorption 157

Table 1.Individual results obtained for each tubule perfused under nondiuretic and volume-expanded conditions8

Control, nondiuretic animals Volume-expanded animals Perfusion Tubule Perfusion Tubule rate length rate length nI/mm mm (CF/PF)urae (CF/PF)1 nI/mm mm (CF/PF)urate (CF/PF) 2.9 1.0 1.37 1.79 4.0 1.6 1.16 1.62 7.4 1.1 1.29 1.45 4.8 1.8 1.56 3.20 7.5 1.1 1.43 1.87 5.5 2.0 1.26 2.49 8.8 2.6 1.64 2.94 6.7 2.1 1.18 1.75 9.4 1.7 1.63 2.40 7.0 1.3 1.23 1.56 9.8 1.2 0.96 1.39 8.6 1.7 1.37 1.49 11.3 1.5 1.14 1.43 10.5 1.2 0.98 1.11 11.9 1.5 1.34 1.50 10.7 1.5 1.05 1.28 14.0 2.7 1.51 1.79 10.8 1.1 1.11 1.19 15.4 2.3 1.45 1.71 10.8 1.6 1.17 1.46 16.0 1.3 1.10 1.25 — — — — 17.3 2.0 1.10 1.30 16.4 2.2 1.30 1.36 17.4 2.5 1.48 1.81 16.6 1.6 1.13 1.38 17.9 2.3 1.25 1.56 17.5 2.5 1.38 1.71 18.1 2.2 1.64 1.89 18.4 1.5 1.13 1.25 18.3 0.8 1.09 1.15 18.5 2.2 1.09 1.47 19.3 2.5 1.26 1.34 19.3 2.2 1.20 1.38 22.6 2.3 1.15 1.30 24.0 2.0 1.08 1.21 22.6 2.0 1.30 1.53 24.3 1.4 1.18 1.24 23.0 1.4 1.62 1.68 25.6 1.0 1.13 1.13 23.7 1.6 1.24 1.34 26.3 2.1 1.01 1.33 24.4 3.4 1.22 1.64 26.6 2.0 1,09 1.18 25.0 2.0 1.30 1.46 27.6 1.8 1.15 1.15 25.4 1.5 1.35 1.54 27.6 1.5 1.13 1.13 26.3 1.4 1.19 1.30 28.3 2.5 1.41 1.54 26.4 2.4 1.29 144 28.8 1.5 1.09 1.14 26.9 1.7 1.31 1.34 29.1 2.0 1.14 1.20 27.8 1.4 1.21 1.30 30.0 1.5 1.07 1.15 27.8 2.1 1.30 1.37 32.7 2.0 1.16 1.15 29.6 1.7 1.43 1.46 32.9 1.3 1.07 1.12 30.8 2.6 1.02 1.34 34.8 0.8 1.04 1.05 31.2 2.4 1.25 1.27 — — — — 31.8 3.5 1.77 1.82 — — — — 31.9 1.8 1.11 1.18 — — — — 33.9 2.7 1.61 1.66 — — — — 35.7 1.9 1,25 1.26 — — — — 38.5 1.6 1.07 1.20 — — — —

Mean SEM 21.7 1.4 1.94 0.13 1.31 0.03 1.53 0.06 19.2 1.7 1.71 0.08 1.17 0.02 1.41 0.08 a CF/PF is the collected fluid to perfusion fluid disintegrations per minute of urate or inulin, respectively. between fractional urate absorption and the per- tional rate of water absorption in response to altera- fusion rate (y = 39.6e°'°856' was not significantly tions in the perfusion rate parallel the values ob- different from values obtained with the perfusion tained in the control animals, but are significantly solution containing 1.3 mg/dl of urate. Water ab- lower at any rate of perfusion (y =33.9e°'555", sorption was similar in both sets of data and not sig- 0.001 compared with control). nificantly different from values summarized in Fig. The relationship between perfusion rate and urate absorption in nondiuretic and volume-expanded an- The relationship between the fractional absorp- imals was also determined with a perfusion solution tion of urate and water and the perfusion rate in vol- containing probenecid in a concentration of 2.8 mgI ume-expanded animals is shown in Fig. 3. The dl (104M). There was no statistical difference in curves of best fit from the control observations de- fractional urate absorption between the two groups picted in Fig. 1 are included for comparison. The of animals. As compared with results obtained relationship between fractional urate absorption when the microperfusion solution did not contain and perfusion rate in this group of animals is de- any drug, at any given rate of perfusion, there was a scribed by the equation y =26.0e°'°761"(P =NS 42% decrease in fractional absorption of urate when compared with control). The changes in the frac- probenecid was present in the microperfusion solu- 158 Scnekjian el a!

30 — 40 —

U rate — — — 0 NaCI + urate (1.3 mg/dl( S S • NaCI + urate (10 mg/dl( 20 . 30 — 0 a, 0 '0 0 0 C . 10 — 020 — . C. E 0 0 . .5 '0 C 0 0 . 0 SS 0. 0 10 — 0 0 .0 10 20 30 40 U- S 0 C 0 50 050 0 0S S 0 S S U- Water 40 Th 10 20 30 40 Perfusion rate, n//rn in Fig.2. Relationship between perfusion rate and fractional urate absorption with varying concentrations of urate in the perfusion solution. Points represent individual perfusions containing urate in concentrations of 1.3 mg/dl (open circles) or 10 mg/dl (closed circles). The lines of best fit are also included for the solution containing urate in a concentration of 1.3 mg/dl (dashed line) and 10 mg/dl (solid line).

0 10 20 30 40 differing results are reported with these different Perfusion rate, n//rn/n methods [9, 10]. On the other hand, previous stud- Fig.1. Relationship between perfusion rate and the rate offrac- tional absorption ofurate(upper panel) and water (lower panel) ies from this laboratory and other laboratories [3, 9, in nondiuretic animals. Each point represents an individual mi- 10], as well as the results of the current study, sug- croperfusion of a proximal convoluted tubule. Solid lines repre- gest that the concentration of urate in the micro- sent the curves of best fit for all the data points. Isotonic saline containing urate in a concentration of 1.3 mg/dl was used as the perfusion solution does not affect the fractional rate perfusionsolution. of [2-'4C]-urate absorption. Thus, when fractional urate absorption is calculated in the manner used in the current studies, the results derived are inde- tion(P <0.001). This result is in accord with more pendent of any secreted unlabeled urate, do not re- extensive prior studies from this laboratory [8] and quire the determination of urate concentration in indicates that, in volume-expanded animals as in the collected fluid, but do reflect changes in the ab- the nondiuretic animals, some component of urate sorptive flux for urate. absorption is inhibitable by inclusion of probenecid We previously demonstrated that at least part of in the microperfusion solution. the urate absorptive mechanism is related to the tubular absorption of hexose sugars [8]. We also ad- Discussion vanced evidence that a second urate absorptive These studies are designed to examine further the mechanism is characterized by its sensitivity to in- determinants of fractional urate absorption from the hibition by probenecid [8]. The current studies in- rat proximal tubule. The net or unidirectional trans- dicate yet another important determinant of urate port rate of urate cannot be calculated from the reabsorption, namely the tubular flow rate. As shown sults of the current studies that use an isotopic in Fig. 1, in nondiuretic animals there is a decline in marker for urate. To calculate either of these rates, the fractional rate of [2-'4C]-urate absorption per we need a specific determination of the chemical millimeter of perfused tubule as the perfusion rate is concentration of urate in the collected perfusate. increased from 3 to 33 nllmin. This decrease in frac- Although methods for determining the concentra- tional urate absorption is probably not a function of tion of urate in nanoliter quantities are available, an increase in the tubular load of urate presented to F/wi' rate and ECV effecton urate and Habsorption 159

30 — Urate 0 increasein the fractional excretion of urate in the final urine [12]. Similarly, free-flow micropuncture 0 studies show that increasing the plasma concentration of urate results in an increased fractional deliv- 20 — eryof urate out of the late proximal tubule as com- 0 pared with nonurate-loaded animals [13]. The results of these studies, in conjunction with those of the present investigation, would seem to indicate 00 0 10 — 0 thatthe increase in fractional excretion noted in S 0 urate-loaded animals could be due to an effect on 0 urate absorption in portions of the nephron other 0 0 0 0 than the superficial proximal tubule. It is more 0 I I I however, that urate loading increases the se- 00______I II -j______likely, .0 0 10 20 30 40 cretory flux for urate, as suggested from studies in = man, by Steele and Rieselbach [14] and in the rat by 050 - 0 deRougemont, Henchoz, and Roch-Ramel [13]. As '0 \Nater U- noted earlier, alterations in the rate of secretion 40 would not be detected by the measurements of urate absorption used in the present studies. 30 Elucidation of the importance of the flow rate on urate absorption led to a reconsideration of the effects of expansion of the ECV with isotonic saline on urate excretion. Expansion of the extracellular 10 volume with saline results in a marked increase in the rate of flow in the proximal tubule [15, 16]. Also, c I I I I I I the infusion of saline decreases urate absorption 0 10 20 30 40 Perfusion rate, ni/mm and enhances its excretion [1—4]. The mechanism of Fig.3. Relationship between perfusion rate and the rate offrac- this response, however, is unknown. An important tionalabsorption ofurate (upper panel) and water (lower panel) prediction from the results obtained in the control in volume-expanded animals. Each point represents an individ- animals would be that if the decreased fractional ab- ual microperfusion of a proximal convoluted tubule, with isotonic saline containing urate in a concentration of 1.3 mg/dl as the sorption of urate seen in volume-expanded animals perfusion solution. Solid lines representing the curves of best fit is solely a function of the rate of flow in the tubular from the control, nondiuretic animals are included for com- lumen, microperfusion of individual nephrons in parison. control and volume-expanded animals at the same perfusion rates should yield similar rates of reabsorption. As shown in Fig. 3, the fractional rate of the tubule, because our prior studies indicate that urate absorption in control and volume-expanded the fractional rate of urate absorption is not altered animals at any given perfusion rate was, in fact, the if the concentration of urate is increased in the pres- same. This would suggest that the increase in tubu- ence of a constant perfusion rate [5]. This finding is lar flow rate induced by expansion of the extra- further confirmed by the results of the current stud- cellular fluid volume is a factor in the decreased ab- ies (Fig. 2) as well as by the findings of Lang, Greg- sorptive flux of urate under these experimental con- er, and Deetjen [9], Roch-Ramel et al [10], and ditions. Implied in this conclusion is that expansion Kramp, Lassiter, and Gottschalk [3], who demon- of the extracellular fluid volume itself does not de- strated that the reabsorptive flux of urate from the crease the intrinsic absorptive capacity for urate in proximal tubule of the rat is not influenced by the the proximal convoluted tubule. The methodology initial concentration of urate. Thus, some parame- used in the current investigations does not permit ter of flow rate has a significant effect on the frac- any estimate of the rate of urate backflux from the tional absorption of urate. A similar effect of flow interstitium into the tubular lumen. Because volume rate on urate reabsorption in the loop of Henle has expansion enhances the backflux of sodium as well previously been reported [11]. as other substances, it is still possible that, follow- Prior clearance studies in the rat demonstrate that ing expansion of the extracellular fluid volume, part raising the plasma urate concentration results in an of the increased urinary excretion or urate is the 160 Senekjian ci a! consequence of enhanced urate backflux into the cribed to the influence of flow rate on proximal tubular lumen [17]. tubular absorption. The current studies would also The results of the present studies differ from prior indicate an important influence of luminal flow rate studies with similar techniques from this laborato- on the absorption of water in the proximal tubule, ry, in that the fractional rates of urate absorption especially under nondiuretic conditions. are lower than those previously reported [5]. The As seen in Fig. 3, when the extracellular fluid vol- perfusion solution in our prior studies contained, in ume is expanded, other factors in addition to altera- addition to sodium chloride, bicarbonate, potas- tions in the luminal flow rate can affect water ab- sium, and glucose. Recent studies from this labora- sorption. In volume-expanded animals at any given tory indicate that the presence of glucose in the rate of perfusion, water absorption was 30 to 40% tubular lumen inhibits urate absorption [8]. Thus, lower than it was in nondiuretic control animals. In the differences between the studies can not be ex- a somewhat analogous study, Bartoli and Earley plained by the presence or absence of glucose. The have reported that expansion of the extracellular discrepancies between the present studies and fluid volume results in a 38% decrease in the ab- those previously published are therefore unex- sorptive capacity of the proximal tubule when de- plained at present. It is interesting, however, that termined by in vivo microperfusion techniques with the trend toward lower rates of urate absorption ob- a constant rate of perfusion [23]. In the same study, served in the present studies has also been evident free-flow micropuncture results indicate that net in intratubular microinjection and clearance studies reabsorption is decreased to an even greater degree, performed in this laboratory. As noted above, the a finding felt to be the result of the increase in single explanation for the lower rates of absorption noted nephron filtration rate. In the present study in vol- in recent studies in unknown, but the findings high- ume-expanded animals, an influence of flow rate on light the importance of obtaining concomitant new water absorption is still evident. In volume-ex- control observations with each set of experimental panded conditions, then, the decrease in the rate of observations. water absorption in the proximal tubule under free- The second aspect of the current study is a reex- flow conditions is due in large measure to a de- amination of the effect of flow rate on water absorp- crease in the absorptive capacity of the tubule, and tion in the proximal tubule under nondiuretic and is contributed to by the increase in the luminal fluid volume-expanded conditions. Over the past dec- flow rate. ade, the factor or factors responsible for the cou- pling between the rate of filtration and the rate of Acknowledgments reabsorption in the proximal tubule have been stud- A portion of this work was presented at the meet- ied extensively. At one time or another, glomerular ing of the American Society of Nephrology held tubular balance has been ascribed to the effects of November 20-21, 1978, in New Orleans, Louisiana, flow rate [18], changes in tubular geometry [19], the and appeared in abstract form on page l47A of the influence of physical factors operative at the con- book of abstracts of that meeting. These studies traluminal side of the renal tubular cells [20], the were supported by the Veterans Administration. generation of hormonal substances thought to influ- Dr. Knight is a Research Associate of the Veterans ence sodium reabsorption in the proximal tubule Administration. Secretarial assistance was given by [21], or the composition of the fluid in the tubular P. Dunham, and technical assistance was given by lumen [22]. Evidence has been marshalled both for D. Steplock, B. Moore, and E. Pace. Dr. Wadi N. and against a dominant role for each of these factors Suki provided guidance and critical review of these under specific experimental circumstances. In the experiments. Dr. John Thornby of the Houston VA present studies in nondiuretic animals, the only var- Medical Center Biostatistics Department provided iable was the perfusion rate. As summarized in Fig. the regression equations and statistical analysis of 1, the fractional rate of water absorption varied in- the data. versely as a function of the rate of perfusion. A large number of prior studies in several species of Reprintrequests to Dr. E. J. Weinman, Renal Section, De- partrnent of Internal Medicine, VA Medical Center, Houston, animals and with a variety of experimental tech- Texas 77211, USA niques have examined the influence of tubular flow rate on the absorptive capacity of the proximal tu- References bule [23—30]. In some studies, alterations in flow 1. WEINMANEJ.EKNOYANG.SUKIWN:The influence of the rate are ascribed only a small role. In more recent extracellular fluid volume on the tubular reabsorption of uric studies, especially those of Bartoli, Conger, and acid. JClin invest 55:283—291. 1975 Earley [25], a somewhat more important role is as- 2. ABRAMSONRG. LEVITT MF:Use of pyrazinamide to assess F/ow rate and ECV effect on urate and H20 absorption 161

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