OBJECTIVE 4: TO UNDERSTAND HOW AN OSMOTICALLY CONCENTRATED URINE IS FORMED BY THE COUNTERCURRENT MECHANISM.

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A. The kidney also has the ability to increase fractional water reabsorption so that it exceeds fractional solute reabsorption. The urine volume can be reduced to less than 1 L/day and the solute concentration may approach 1200-1400 mosmole/kg H₂O. The concentration process is much more complex than the dilution process and involves much more than increased secretion of ADH and a high permeability of the tubular epithelium to water. Basically, the osmotic gradient created across the epithelium of the thick ascending limb by active salt transport is conserved and multiplied by the countercurrent flow of urine in the loop of Henle and of blood in the medullary capillaries. This countercurrent osmotic gradient then drives water reabsorption from the collecting tubule.

B. The countercurrent principle is most easily illustrated by considering a furnace (Fig. 7-4) in which the fresh air duct lies side by side with the exhaust duct so that fresh air, entering the furnace, flows counter to and in close proximity to the exhaust fumes. The cold air flowing into the furnace receives heat from the exhaust fumes, and a small horizontal temperature gradient between the two pipes is "multiplied" into a large vertical gradient. The air entering the furnace arrives at a high temperature and the heat that could have been lost in the exhaust is conserved, thereby improving the efficiency of the furnace.

Fig. 7-4. An illustration of the use of the countercurrent principle to conserve heat and improve the efficiency of a furnace. The thick arrows indicate the direction of heat flow.

C. The countercurrent system works within the confines of the medulla. The important anatomical feature is the long hairpin construction of the loops of Henle and the capillaries, the vasa recta, which provide the "countercurrents". The tubular fluid and blood flowing up and out of the medulla run counter to and in close proximity to tubular fluid and blood flowing down into the medulla. The collecting tubules bring a smaller volume of the tubular fluid back down from the cortex through the medulla. Salt transport out of the ascending limb of Henle's loop alters the composition of the ISF and in turn the interstitial fluid alters the composition of the fluid in the descending limb of Henle's loop and in the collecting tubule.

D. The loop of Henle is called the "countercurrent multiplier". The "furnace" for the countercurrent system is the active transport mechanism for salt in the ascending limb of the loop (Fig. 7-5, See also fig. 6-6). It removes solute from the tubular fluid and deposits it in the medullary ISF.

Fig. 7-5. The loop of Henle, the "countercurrent multiplier." The numbers indicate the osmotic concentration. The large circles to the right represent cross-sections of the medulla. Dlh, alh = descending and ascending limbs of Henle=s loop.

1. The impermeability of the tubular epithelium to water prevents water from following the solute, so the osmotic concentration of the tubular fluid is reduced and the concentration of the ISF is raised. It is this initial, small, horizontal gradient (approximately 200 mosmole/kg, see circles in Fig. 7-5) across the tubular wall that is "multiplied" vertically along the length of the loop by countercurrent flow.

2. The hyperosmotic concentration of the ISF then causes water to move out of the descending limb, thereby progressively raising the concentration of the remaining tubular fluid as it flows toward the tip of the loop.

3. Na and Cl diffuse from the medullary ISF down their chemical gradients back into the tubular fluid in the descending limb. This also serves to increase its osmotic concentration.

4. After the fluid flows around the bend and starts back up in the ascending limb, Na and Cl, but little water, are removed and fluid becomes more and more dilute as it approaches the distal tubule. Thus Na and Cl are trapped and recycled in the medulla.

5. Note that fluid enters the medulla in the descending limb with an osmotic concentration of 290 mosmole/kg H₂O and leaves the medulla in the ascending limb with an osmotic concentration of about 100. More solute than water has been removed from the tubular fluid by the loop. This excess solute is deposited in the medullary ISF, raising its osmotic concentration. This creates the osmotic force which causes water to move out of the other structures in the medulla.

E. The distal tubules in the cortex and the cortical collecting tubules receive the hypo-osmotic tubular fluid from the loop of Henle and, in the presence of ADH, transport the excess fluid into the cortical ISF (Fig. 7-6). Thus the solute free water, formed by salt reabsorption in the medulla, is returned to the systemic circulation and a much smaller volume of isosmotic tubular fluid reenters the medulla via the collecting tubules. Note that the water reabsorbed in the cortex, from the distal tubule and cortical collecting tubule, dilutes the systemic blood, reducing its osmotic concentration.

F. The target of the final effect of the countercurrent mechanism is the medullary collecting tubule (Fig.7-6). As the tubular fluid flows down the medullary collecting tubule, it comes into contact through the tubular epithelium with the hyperosmotic medullary ISF. In the presence of ADH, water is reabsorbed in excess of solute and the tubular fluid becomes increasingly concentrated as it approaches the papilla. This is the final effect of the countercurrent process, the return of water to the circulation and the osmotic concentration of the urine.

Fig. 7-6. The role of the distal tubule and collecting tubule
 in the countercurrent process. CD = collecting tubule.

G. The vasa recta serve as countercurrent exchangers and conserve the composition of the medullary interstitium while providing nutrients to the cells (Fig. 7-7). If the blood vessels in the medulla were anatomically similar to those in the cortex, they simply would carry away the salt transported out of the ascending limb of the loop and the countercurrent gradient could not exist. However, the hairpin construction of the vasa recta, coupled with a blood flow rate that is much slower than the flow rate in the cortex, allows blood to flow through the medulla without causing more than a minimal disturbance in the osmotic gradient.

1. Plasma, entering the descending limb of the vasa recta with the usual systemic osmotic concentration of 285-290 mosmole/kg H₂O, comes into contact through the capillary wall with the high Na, Cl and osmotic concentration of the medullary ISF. Water flows out of the descending limb in response to the osmotic gradient and Na and Cl diffuse in. Thus the plasma becomes increasingly more concentrated as it approaches the tip of the papilla.

Fig. 7-7. The vasa recta, the "countercurrent exchanger." Dvr, avr = descending and ascending vasa recta.

2. As this concentrated fluid flows into the ascending limb of the vasa recta and back toward the cortex, it encounters interstitial fluid that is more dilute than it is. Water then flows down the osmotic gradient into the ascending vasa recta and Na and Cl diffuse out.

3. This countercurrent flow of blood preserves the high solute concentration of the medullary ISF. Excess water is kept out of the medulla since it tends to "short-circuit" the loop by leaving the dilute incoming plasma and flowing into the more concentrated plasma leaving the medulla. In addition, most of the solute deposited in the medulla by the loop of Henle recycles from the ascending to the descending vasa recta and is trapped in the medulla.

4. The trapping of solute is not complete and the rate at which solute is carried out of the medulla by the vasa recta exceeds that carried in. In addition water, reabsorbed from the descending limb of the loop and from the collecting tubule, is carried out by the vasa recta. Thus the volume and osmotic concentration of the exiting plasma exceed that of entering plasma. The rate of leakage of solute out of the medulla via the vasa recta increases as the osmotic concentration of the ISF increases until a steady state is achieved when, at some high osmotic concentration of the ISF, the rate of solute transport out of the thick ascending limb is balanced by the rate of solute leakage into the exiting plasma.

H. Urea also plays a major role in the concentration of the urine. The countercurrent system can concentrate urea in the medullary ISF and in the tubular fluid. A reduction in the supply of urea to the kidney reduces the effectiveness of the countercurrent trapping of NaCl in the medullary ISF and decreases the concentration of non-urea solute in the final urine.

1. The source of most of the urea in the medullary interstitium is the inner medullary collecting tubule (Fig. 7-8). Tubular fluid arriving at that point has a very high urea concentration because the fractional reabsorption of water has greatly exceeded the fractional reabsorption of urea in more proximal urea-impermeable structures. The inner medullary collecting tubule is permeable to urea and there is a chemical gradient for passive diffusion of urea into the medullary ISF. This passive reabsorption is stimulated by ADH. Urea then diffuses from the ISF into the vasa recta and is trapped in the medulla by this countercurrent exchanger.

2. As the vasa recta blood, high in urea concentration, flows up the ascending capillary it enters a region where the ISF concentration is not as high. Urea diffuses back into the ISF and thence into the descending capillary containing plasma which has a low urea concentration. This trapping and recycling of the urea in the medulla raise the concentration to a high level.

Fig. 7-8. Countercurrent concen-tration of urea by the vasa recta and inner medullary collecting tubules.

3. The high concentration of urea in the ISF adds to the osmotic force drawing water from the descending limb of the loop of Henle and from the collecting tubule. The countercurrent trapping of urea also reduces the gradient for urea diffusion from the inner medullary collecting tubule and permits the kidney to excrete urine with a high concentration of this waste product of nitrogen metabolism.

4. The trapping of urea by the countercurrent system depends ultimately upon active salt transport by the thick ascending limb. It is this transport which sets up the gradients for water reabsorption from the distal tubule and the cortical and outer medullary collecting tubules. That water reabsorption establishes the gradient for urea diffusion out of the inner medullary collecting duct.

1. The longer the loops of Henle in proportion to the rest of the nephron, the greater the vertical osmotic gradient. Some species that live in a dry environment such as the gerbil, the kangaroo rat and the golden hamster possess nephrons with loops so long that the papilla of these animals protrudes into the ureter. These animals may excrete urine with a concentration of 4000-5000 mosmole/kg H₂O.

2. ADH controls the permeability of the collecting tubule to water. If the hormone is present in reduced amounts or is absent, the tubule becomes effectively impermeable to water and the tubular fluid osmolality falls as solute is reabsorbed. Its presence is required for the countercurrent system to be effective. The hormone stimulates urea reabsorption from the inner medullary collecting duct and may also stimulate salt reabsorption in the thick ascending limb.

3. An increase in a flow rate through the ascending limb of the loop of Henle increases salt reabsorption by that tubular section. This is a result of the effect of flow rate on the gradient-limited NaCl transport mechanism (Fig. 7-9). The increase in salt transport into the medullary ISF raises its osmolality. Flow rate to the thick ascending limb can be increased by a rise in GFR or by inhibition of salt and water reabsorption in the proximal tubule.

4. An increase in flow rate through the medullary collecting tubule tends to decrease the effectiveness of the countercurrent system. As flow into the collecting duct increases, more water is initially reabsorbed into the medullary ISF and decreases its osmolality. As the medullary ISF osmolality declines, the rate of water reabsorption from the collecting tubule falls. Flow rate through the collecting tubule can be increased by inhibition of reabsorption in the distal tubule and at other points upstream. Maximum urine osmotic concentrations are achieved when the ratio of loop flow rate to collecting tubule flow rate is high.

5. An increase in the rate of blood flow through the medullary capillaries increases the rate at which solute is carried out of the medulla and reduces the effectiveness of the countercurrent system. It is difficult to assess the importance of this factor because this blood flow rate is very difficult to measure.

6. As indicated above, factors that influence the concentration of urea in the filtrate affect the countercurrent system. An insufficient intake of protein can reduce the supply of the urea and reduce the ability of an animal to cope with a low intake of water.

7. A number of drugs affect the countercurrent system. The primary driving force for the countercurrent system is the active transport of salt out of the thick ascending limb. Inhibition of this transport disrupts the countercurrent system. Furosemide, ethacrynic acid, and bumetanide ("loop diuretics") have this effect. Inhibition of solute reabsorption in the distal tubule increases the flow rate into the collecting tubule and thereby interferes with the countercurrent mechanism. Amiloride, the thiazide diuretics and aldosterone inhibitors such as spironolactone have this effect.

QUESTIONS:
6. What force causes water reabsorption in the thin descending limb of the loop of Henle? Does Na cross the tubular epithelium? In what direction? How?

7. What combination of membrane properties and transport processes causes the tubular fluid in the thick ascending limb of the loop of Henle to become more dilute than the surrounding interstitial fluid?

8. What is the primary generating force of the countercurrent system? What is the effect of transport by the loop of Henle on the composition of the medullary interstitial fluid? How is the effect of salt transport by the thick ascending limb "multiplied" into the large cortex-to-papilla osmotic gradient? How does the removal of solute from the tubular fluid in the thick ascending limb of the loop of Henle result in a concentrated tubular fluid in the collecting duct?

9. Why does water reabsorption by the distal tubule and collecting tubule in the cortex contribute to the maintenance of the high osmotic concentration of the medullary interstitial fluid?

10. In what two ways does the countercurrent arrangement of flow in the vasa recta serve to preserve the concentration of solute in the medullary interstitial fluid?

11. If urea is reabsorbed in the proximal tubule, why does its concentration in the tubular fluid increase? Why is the concentration of urea in the fluid flowing into the inner medullary sections of the collecting tubule so high? How is the high urea concentration in the medullary interstitial fluid established?

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