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Journal of Physiology (2001), 536.2, pp. 533-539
© Copyright 2001 The Physiological Society
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ABSTRACT |
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INTRODUCTION |
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Drainage of interstitial fluid by lymph vessels is generally considered essential for maintenance of fluid balance across the capillary wall. If lymph flow stops, capillary fluid filtration will continue and increase interstitial volume. Low compliance and build-up of interstitial pressure may limit expansion, but continued leakage of plasma protein from capillary plasma will increase interstitial colloid osmotic pressure and prevent absorption of fluid. In spite of this recipe for development of lymph oedema, several organs and tissues, such as the brain, cornea and bone marrow, do well without lymph vessels (Aukland & Reed, 1993), by removing plasma proteins from the interstitium by some other route, or by local catabolism of the protein (Casley-Smith, 1982). In the kidney, there are many lymph vessels in the cortex and probably some also in the outer medulla, but the most careful anatomical studies have failed to identify lymph vessels in the inner medulla, including the papilla (Kriz & Dieterich, 1970; O'Morchoe, 1985). Since it has been shown that labelled macromolecules are rapidly taken up in the medullary interstitium from the bloodstream (Lassen et al. 1958; Moffat, 1969), protein must be drained off by some other route. Two possibilities can be considered: (1) diffusive or convective transport of protein through the papillary interstitium to the outer medulla where it is taken up by lymph vessels and (2) convective inflow of protein into plasma resulting from fluid transport from collecting ducts to the vasa recta.
To distinguish between these possibilities we have studied the rate of removal as well as the escape route of 125I- and Evans-blue-labelled albumin deposited in the papillary interstitium in rats, firstly by locating the labels at varying times after infusion, and secondly by recording their appearance in systemic plasma and the renal lymph. In preliminary experiments we observed complete disappearance of Evans blue-albumin within a few minutes (Tenstad et al. 1988), an observation which was later confirmed by MacPhee & Michel (1995a). The extension of those experiments provided strong evidence that albumin is taken up locally by the vasa recta and does not enter any renal lymph vessel.
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METHODS |
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Female Wistar-Møller rats weighing 80-180 g were anaesthetized with Inactin, 100 mg (kg body weight)-1 intraperitoneally, and kept on a servo-controlled heating pad. The rats were tracheotomized and polyethylene catheters were inserted into the right carotid artery for blood sampling and in the right femoral vessels for I.V. infusions and continuous recording of arterial blood pressure. Saline was infused at a rate of 0.5 ml h-1 (100 g)-1 throughout the experiment. The left kidney was exposed through a flank incision, freed from perirenal fat and placed, with its dorsal surface facing upwards, in a plastic cup with a wide fissure for the renal pedicle. The kidney was embedded in and covered with cotton wool soaked in mineral oil. At the end of the experiment, the rat was killed by I.V. injection of 0.5-1 ml saturated KCl. All experiments were performed in accordance with recommendations given by the Norwegian State Commission for Laboratory Animals and were approved by the local ethical committee at the Department of Physiology, University of Bergen.
Albumin tracer
Human 125I-albumin stock solution containing 2 mg albumin ml-1 and 17 MBq 125I ml -1 was purchased from the Institute of Energy Technology, Kjeller, Norway. Free radiolabel was estimated by trichloroacetic acid precipitation and accounted for less than 2 % of the total radioactivity. Prior to infusion into renal tissue,125I-albumin was coloured with Evans blue (0.2 mg ml-1). For papillary infusion, the osmolarity was increased to about 500 mosmol l-1 by addition of NaCl.
Lymph collection
Lymph was collected either from the thoracic duct or from a renal hilar lymph vessel. The thoracic duct was accessed extrapleurally through a midsternal incision (Reinhardt, 1945) and cannulated by PE-50 tubing just prior to its entrance into the subclavian vein. The distal end of the catheter was placed under mineral oil in a 1 ml Eppendorf centrifuge vial 1-2 cm below the thoracic duct outflow level. The thoracic duct lymph flow ranged from 2 to 20 µl min-1.
All visible renal hilar lymph vessels were tied off close to their entry into the lymph nodes using 7-0 ligature thread. Most of the prenodal lymph vessels expanded rapidly upon ligation and the largest was chosen for cannulation. A polypropylene tubing was pulled out to an outer diameter of about 0.2 mm and filled with undiluted heparin. Lymph began to flow into the 5-10 cm long catheter immediately upon successful cannulation and was collected in glass capillaries. The flow ranged from 0.2 to 1 µl min-1.
Washout or movement of 125I-albumin deposited in the papillary interstitium
The extrarenal papilla was exposed through a pelvic incision, and supported and transilluminated by a fibre optic plexiglass rod. A sharpened micropipette with tip diameter of 2-8 µm was connected to a pressure-controlled pump. The pump tubing was filled with mineral oil, and ended in a pipette holder mounted on a micromanipulator. The distal end of the micropipette was filled with 1-2 µl albumin tracer solution by suction from a droplet placed under mineral oil. Similarly, about 0.1-0.2 µl of 0.5 M saline was sucked up into the pipette tip to avoid leakage of tracer albumin during pipette insertion. Using a Wild stereomicroscope (Wild, Heidelberg, Germany; magnification 
40), the pipette was slowly advanced into the transilluminated papilla, avoiding as far as possible the vasa recta, loops of Henle and collecting ducts. The pump pressure was then increased slowly up to 50 mmHg until a spherical, diffusely coloured area appeared around the pipette tip, indicating infusion of 125I-albumin tracer to the papillary interstitium. The pressure was then rapidly reduced to a level of 5-20 mmHg to sustain a coloured area in the papillary tissue of about 50 µm in diameter. When a steady depot had been obtained for 5 min, the infusion was stopped, the pipette pulled out and the kidney rapidly removed after 15 s (n = 10), 60 s (n = 9) and 150 s (n = 9) and frozen in ethanol pre-chilled to about -50 °C (Fig. 1A).
The frozen kidney was transferred to a Petri dish containing ethanol placed on a hollow metal plate kept at -8 to -10 °C, and the kidney poles were cut off perpendicularly to the long axis leaving a slice about 4 mm thick containing the papilla. The cortex and some medullary tissue of the dorsal and ventral aspects were removed yielding a pyramidal-shaped tissue block with the papillary tip as apex and the remaining cortex as the basis. From this tissue block the cortex and outer medulla were cut off and the remaining inner medulla was divided into three sections of similar thickness along the cortico-papillary axis. The outer medulla was cut off from the paler inner medulla (about 4-5 mm from the papillary tip), and the inner medulla was subdivided into three pieces, IM 1-3, as shown in Fig. 1. The three samples were rapidly transferred to tarred vials, weighed and counted in a LKB gamma counter (Wallac, Turku, Finland).
Uptake in blood and lymph following 125I-albumin infusion into the papilla
In this series of experiments, the rats (n = 11) were prepared as described previously except that the pelvis was left intact to prevent contamination and peritoneal lymphatic uptake of tracer derived from pierced collecting ducts or loops of Henle during micropipette insertion. Direct puncture of the papilla through the pelvic wall was made possible by paralysing the pelvis by topical application of verapamil (Oliver et al. 1982). Urine was collected by polypropylene tubing pulled out to an appropriate outer diameter and introduced through the initial part of the ureter. The micropipette was filled with 1-2 µl tracer as described previously, but was now connected to a micro-syringe pump. The paralysed pelvis was punctured and the pump started at a rate of 2-10 nl min-1. When the coloured 125I-albumin appeared in pelvic urine, the pipette was slowly advanced into the papillary tissue until a spherical, diffusely coloured area appeared around the pipette tip. The flow rate was adjusted to maintain a coloured area in the papillary tissue of about 50 µm in diameter for 60 min. Arterial blood and thoracic duct lymph was collected every 10-15 min during the infusion and the following washout period of about 2 h.
Uptake of 125I-albumin in blood and lymph following albumin infusion into the cortex
In this series of six rats albumin tracer was infused into the renal cortex through a polypropylene catheter with an outer diameter of 0.1-0.2 mm. A small hole was made in the renal capsule with a round steel needle (0.2 mm diameter) which was then carefully advanced in between the tubules, making a shallow groove in the renal cortex beneath the intact capsule. Thereafter, the catheter was advanced into the blind end of this subcapsular channel and pushed a little further into the renal parenchyma and connected to a constant pressure pump. The renal capsule was sealed by Histoacryl tissue glue (B. Braun, Melsungen, Germany) and the kidney was allowed to recover for about 15 min. Cortical 125I-albumin infusion was started by increasing the pump pressure until a blue area appeared around the tip of the catheter. The pressure necessary to initiate movement of tracer into the cortex ranged from 10 to 80 mmHg and resulted in a flow ranging from 3 to 50 nl min-1, average 16 nl min-1. Arterial blood and thoracic duct lymph was collected every 10-15 min during the 60 min infusion period and the following washout period of about 2 h. (The use of pressure versus volume-controlled infusion in cortex and papilla does not reflect a selective preference for the two techniques, but rather that the constant volume infusion pump became available after the constant pressure device.)
Albumin infusion into the renal vein
Uptake of 125I-albumin in the thoracic duct lymph following a 60 min infusion into the renal vein at a rate of 5 nl min-1 was investigated in six rats. Arterial blood and thoracic duct lymph were collected at 10-15 min intervals and the experiment was completed 3 h after starting infusion into the renal vein.
Albumin infusion into a renal hilar lymph vessel
One hilar lymph vessel of the left kidney was micropunctured in two rats and 1 µl Evans blue-coloured 125I-albumin solution was infused in the course of about 10 min. The thoracic duct lymph was continuously collected and arterial blood was sampled just prior to lymph vessel puncture, a few minutes later and then about 70 min after completion of the 125I-albumin infusion.
Statistics
Data are presented as mean ± 1 S.E.M. Mean values were compared using Student's t test. P < 0.05 was considered statistically significant.
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RESULTS |
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The pipette was inserted blindly into the papillary tissue, and advanced slowly while infusing tracer. Successful tracer deposition in the interstitial space was judged by the appearance of a spherical zone of dye around the pipette tip. Infusion during pipette insertion into the papilla resulted in one or more thin coloured stripes in the papillary tissue (2-10 µm in diameter) extending from the pipette towards the papillary tip and the cortex. Most of these stripes faded within a few minutes. Appearance of 125I activity in the urine indicated that some loops of Henle and collecting ducts had been punctured, in agreement with previous observations (Oliver et al. 1982). On the other hand, 125I-albumin infused into the pelvic urine through the intact pelvis, could not be detected in the plasma or lymph, indicating that 125I-albumin contamination in loops of Henle or collecting ducts is not taken up into plasma or lymph. Since a variable amount of 125I activity was found in urine (58 ± 8 and 34 ± 20 % after injection into the papilla and cortex, respectively), the uptake into lymph and plasma was always estimated as the fraction of the total amount accumulated in the lymph and plasma. The plasma content of 125I-albumin was calculated as the concentration in plasma at the end of the 60 min papillary infusion multiplied by a plasma volume of 4 % of body weight.
Washout of 125I-albumin deposited in the papillary interstitium
The coloured area around the pipette tip following a 5 min infusion of Evans blue- and 125I-labelled albumin into the renal papillary interstitium disappeared completely within 1-2 min after infusion stopped, with no visible preferential movement towards the cortex. In an attempt to obtain quantitative estimates of the apparently rapid clearance of labelled albumin from the interstitium, the 125I activity was measured in three zones of the inner medulla (Fig. 1) 15-150 s after the infusion ended.
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Figure 1. Kidney sections and tracer infusion sites A, site of medullary tracer infusion and sectioning of medulla. Radioactivity was measured in three serial sections of the inner medulla (IM 1-3) 0.25, 1 or 2.5 min after completing 125I-albumin infusion into the papillary interstitium (IM 3). B, 125I-albumin infusion sites in a renal hilar lymph vessel, papillary or cortical interstitium. | ||
Figure 2 shows that the half-time of 125I-albumin in the papilla (IM 3) was less than 1 min, in agreement with the rate of visual dye clearance. The content of 125I-albumin in the more superficial zones of the inner medulla (IM 1 and IM 2) was about 20 % of the activity in the papillary tip and most probably represents tracer in stagnant loops of Henle, presumably broken and/or occluded during the positioning of the pipette or in the 5 min infusion period. Due to the larger volumes of IM 2 and IM 3 samples, their 125I-albumin concentration was only 5 % relative to that in the papilla. The similar decay of radioactivity in all three layers of the medulla (Fig. 2) suggests no transfer of radioactivity from the infusion site in the papilla to IM 2 and IM 1 after deposition of the tracer.
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Figure 2. Tracer removal from inner renal medulla 125I-albumin (125I-Alb) activity (mean ± 1 S.E.M.) in the three serial sections of the inner medulla, IM 1 ( | ||
Uptake of 125I-albumin to plasma and lymph during and following local infusion
During a 60 min period of tracer infusion into cortical and papillary interstitium, the plasma concentration of 125I-albumin rose linearly, indicating a constant uptake of locally infused 125I-albumin by peritubular capillaries and the vasa recta (Fig. 3, open symbols). The decrease in plasma radioactivity after infusion stopped reflects the distribution of 125I-albumin into the systemic extracellular fluid and suggests little or no further uptake of interstitial 125I-albumin to the bloodstream beyond the first 2 min after stopping papillary infusion, indicating rapid turnover of the 125I-albumin available for uptake into plasma in both cortical and papillary interstitium.
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Figure 3. Uptake of infused tracer in plasma and lymph 125I-albumin (125I-Alb) activity in the thoracic duct lymph (TDL) (filled symbols) and plasma (open symbols) during and after a 60 min 125I-albumin infusion into the cortical (upper panel) or papillary (lower panel) interstitium in 11 rats (mean ± 1 S.E.M.). Y-axis: [125I-Alb] in the plasma and TDL relative to that in the plasma at the end of the 60 min 125I-Alb infusion. | ||
While the removal of 125I-albumin by blood was similar during local infusion in the cortex and papilla, the uptake in the thoracic duct lymph differed markedly depending on the infusion site (Fig. 3, filled symbols). During cortical 125I-albumin infusion, the radioactivity appeared almost instantaneously in the thoracic duct lymph and exceeded the concentration in plasma about seven times (Fig. 3, 
) indicating mainly lymphatic uptake. 125I-albumin infused into the papilla appeared immediately in the plasma (Fig. 3, 
) and then in the thoracic duct lymph at a lower concentration (Fig. 3, 
), indicating uptake into the thoracic duct lymph of tracer recirculating from blood to extracellular fluid and contaminating lymph from the whole body, but no direct uptake of 125I-albumin injected into the papilla.
Figure 4 shows that: (1) 125I-albumin injected into the renal hilar lymph appeared only in the thoracic duct lymph and not in the bloodstream, indicating that lymph from the left kidney was quantitatively recovered in the thoracic duct lymph; (2) accumulation of 125I-albumin in the thoracic duct lymph after 60 min papillary infusion was only 2.3 ± 0.5 % of the total amount recovered in the thoracic duct lymph and plasma; (3) lymphatic uptake following intravenous infusion (1.7 ± 0.3 %) was not significantly different from that obtained after infusion into the papillary interstitium (P > 0.1), giving no evidence for lymphatic removal of plasma proteins from the medullary interstitium; and (4) 125I-albumin infused into the cortical interstitium was removed both by plasma (80 %) and lymph (20 %).
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Figure 4. Tracer recovery depending on injection site Amount of 125I-albumin (125I-Alb) accumulated in the thoracic duct lymph (TDL) relative to the total amount taken up in the thoracic duct lymph and plasma after 125I-albumin infusion into the renal hilar lymph (RHL) (n = 2), papilla (n = 11), renal vein (RV) (n = 6) and cortex (n = 6). Values are mean ± 1 S.E.M. | ||
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DISCUSSION |
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Plasma proteins in blood flowing into the medulla are concentrated by glomerular filtration, and a further increase in plasma protein concentration, up to 70 % above that in systemic plasma, takes place in the descending vasa recta (Sanjana et al. 1975, 1976; Pallone et al. 1989). This creates a high oncotic pressure in the ascending vasa recta limb which favours uptake of fluid reabsorbed from the collecting ducts, provided that the interstitial protein concentration is kept low. However, such a gradient will also favour diffusive loss through the highly protein permeable ascending vasa recta (Pallone, 1992; MacPhee & Michel, 1995a), creating the need for some means of returning interstitial proteins to the blood compartment. Three possibilities should be considered: (1) lymph drainage by inner medullary lymph vessels (see following paragraph) overlooked in anatomical studies; (2) drainage through the inner medullary interstitium into the outer medulla and/or cortex where protein is taken up by lymph vessels; and (3) convective uptake in the vasa recta.
Medullary lymph vessels are described in several species, but as reviewed by O'Morchoe (1985), more critical investigations including identification by electron microscopy have at most shown a few lymph vessels in the outer medulla but none in the inner medulla (Kriz & Dieterich, 1970; Albertine & O'Morchoe, 1980). Nevertheless, O'Morchoe (1985) concluded that the existence of inner medullary lymph vessels has not been definitively excluded, but their scarcity must be such that they are unimportant.
The present experiments were designed to provide a functional and quantitative description of the drainage route(s) by infusing labelled albumin into the papillary interstitium and watching its disappearance from the infusion site, its potential movement in the medulla and its final appearance in the plasma and lymph. Decisive for confirming the validity of the methods used were the preliminary observations that all lymph from the kidney was drained to the thoracic duct, and that labelled albumin inadvertently injected into the loops of Henle or collecting ducts was quantitatively retained in the intact pelvis and ureter.
By visual inspection it was established that Evans blue-labelled albumin formed a round coloured spot that remained unaltered during constant infusion, but disappeared in 1-2 min when the infusion was stopped, in good agreement with the description given by MacPhee & Michel (1995a). While no lymph vessels or more diffuse spreading to more superficial layers could be observed, the quantitative estimate of 125I-albumin after 5 min infusion showed that small amounts had reached the more superficial layers of the inner medulla, the smallest amount reaching the most superficial part (IM 1). In all layers the clearance was initially rapid, with a half-time of only 40-50 s, and then slowed down in the period 60-150 s after the infusion stopped. The initial rapid fall in tracer concentration in all layers represents removal of 125I-albumin from the injection site though the vasa recta. The slow disappearance following the first minute presumably represents stagnant tracer. Supporting this interpretation, dissection of the medulla several minutes after the end of the infusion revealed radial streaks and patches of dye, apparently representing stagnant loops of Henle. While these observations strongly suggest rapid clearance of 125I-albumin through the vasa recta, a contribution by interstitial transport and lymph clearance could not be definitively excluded.
The decisive evidence against lymphatic clearance from the papilla came from frequent estimates of 125I-albumin in the plasma and thoracic duct lymph during and following constant interstitial infusion through the intact pelvis. As noted previously, an intact and immobilized pelvis was necessary because insertion of the pipette and searching for a position which gave a satisfactory interstitial dye deposition invariably led to filling and draining of some loops of Henle with labelled albumin. With an open pelvis this led to spillage of tracer into the peritoneum and subsequent uptake in peritoneal lymph vessels, as confirmed by rapid recovery in the thoracic duct of 125I-albumin deposited outside the intact renal pelvis and ureter. In contrast, we found a lymphatic fraction of only 0.023 of the totally recovered 125I-albumin following papillary 125I-albumin infusion through the intact pelvis. In fact, this small fraction was not greater than could be accounted for by recirculation of 125I-albumin through the plasma and lymph from all other organs, as shown by a similar thoracic duct fraction of 0.017 after intravenous infusion (Fig. 4).
When interpreting the lymph and plasma concentration patterns resulting from local infusion (Fig. 3), it should be realized that 125I-albumin taken up by lymph vessels is quantitatively collected from the thoracic duct catheter and does therefore not reach the bloodstream (Adair, 1985). It should also be noted that the concentration of albumin drained from the renal interstitium will be low in the thoracic duct lymph compared to that of renal lymph because of dilution by lymph from other organs. If the experimental kidney contributes 10 % of the total thoracic duct flow, the concentration in the renal lymph draining into it would be 10 times greater. On the other hand, albumin drained from the infusion site into the vasa recta will accumulate in systemic plasma and in turn appear at a lower concentration in lymph from all organs, including renal lymph.
If we compare the experiments where tracer was infused into the medullary interstitium with those where infusion was into the cortex, major differences were found. The lymphatic fraction of 125I-albumin infused into the cortex was 21 %. Somewhat surprising, though, was the finding that more than 75 % of the tracer was taken up by the blood vessels in spite of an apparent rich supply of lymph vessels in the cortex (Kriz & Dieterich, 1970; Albertine & O'Morchoe, 1980). The explanation is probably that all cortical lymph vessels are located along the interlobar, arcuate and interlobular arteries, with no vessels penetrating in between the cortical tubules (Kriz & Dieterich, 1970; O'Morchoe, 1985). Since the peritubular capillaries have been shown to be able to sustain a positive interstitial-lumen pressure difference without collapsing and take up fluid according to such a hydrostatic pressure gradient (Aukland et al. 1994), it seems likely that an increase of interstitial pressure caused by the infusion could be responsible for the high plasma uptake. As demonstrated by MacPhee & Michel (1995b), the vasa recta can also withstand a positive interstitial-luminal pressure gradient, and it seems likely that a local pressure increase during infusion may contribute to the rapid vascular uptake. Whether a hydrostatic pressure gradient is responsible for fluid and albumin uptake in the normal state seems rather unlikely.
Another important reason for the substantial uptake in blood may be the high gradient of labelled albumin resulting from local infusion and a virtually one-way diffusion of 125I-albumin from the interstitium to the bloodstream. In this connection it is interesting to note that Szabo et al. (1973) found that 94 % of 125I-albumin reached the bloodstream within 1 min following bolus injection through a cannula blindly introduced into the renal cortex. A similar high blood clearance was observed in skeletal muscle, whereas lymphatic clearance prevailed in several other tissues. The explanation may well be that both muscle and renal lymphatics are located along the arteries and larger arterioles, and do not invade the 'parenchyma' (Schmid-Schonbein, 1990; Aukland & Tenstad, 1995). A nearly unidirectional diffusion of the labelled albumin might contribute, but would seem quantitatively insufficient. At the relatively low plasma flow in the papilla, the removal half-time of less than 1 min would in fact require perfusion-limited transport (equilibrium of plasma and interstitial concentrations during each passage of a blood element), which is highly unlikely for a large hydrophilic molecule like albumin. This agrees well with permeability studies indicating that diffusive transport must be negligible compared to convection (Pallone, 1992; MacPhee & Michel, 1995a).
The present experiments provide no direct information on the forces normally responsible for uptake of extravasated albumin by the vasa recta. A high, local interstitial hydrostatic pressure might well contribute to convective influxes into the vasa recta. In spite of a large scatter, the available data shows that hydrostatic pressure is higher in the vasa recta than in the papillary interstitium, and that the albumin concentration is maintained at a lower level in the interstitium than in vasa recta plasma, even if the protein permeability clearly should allow diffusion out from the vasa recta (for references, see Pallone, 1994; MacPhee & Michel, 1995a). Without lymph drainage, this means that plasma proteins must be returned to plasma against a concentration gradient through convection created by a colloid osmotic gradient driven by the same proteins (Aukland et al. 1994; MacPhee & Michel, 1995a). This 'bootstrap' mechanism (Casley-Smith, 1975; Perl, 1975) will always transport fluid into the plasma with a lower albumin concentration than that in interstitial fluid, and will therefore leave behind an increasing interstitial albumin concentration. However, in the renal papilla, dilution by inflow of protein-free fluid from the collecting ducts will establish a steady state, with continued convective reabsorption of protein equal to the diffusive loss from the vasa recta, as suggested in previous studies (Aukland et al. 1994; MacPhee & Michel, 1995a; Michel, 1995).
Conclusion
We have studied the escape of proteins infused into the papillary interstitium of the kidney to see whether proteins entering the medullary interstitium are removed by diffusion through the papillary interstitium to lymphatics in the outer medulla or by convection to plasma in the vasa recta. While 125I-albumin appeared almost instantaneously in the thoracic duct lymph and exceeded the concentration in plasma by ~7 times after cortical infusion, indicating lymphatic uptake, tracer injected into the papilla appeared almost immediately in plasma, but only after a lag phase and at a lower concentration in the thoracic duct lymph, indicating vascular uptake and recirculation from blood to extracellular fluid. The experiments provide strong evidence that albumin is taken up locally by the papillary vasa recta and does not enter renal lymph vessels. Energetically, the protein removal from the medullary interstitium is driven by the same sodium pump that creates medullary hypertonicity and concentrated urine.
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Acknowledgements
Financial support from The Norwegian Council on Cardiovascular Diseases and The Research Council of Norway is gratefully acknowledged.
Corresponding author
H. Wiig: Department of Physiology, University of Bergen, Årstadveien 19, N-5009 Bergen, Norway.
Email: helge.wiig{at}fys.uib.no
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), IM 2 (
) and IM 3 (