OBJECTIVE 5: TO UNDERSTAND THE CAUSES OF SOLUTE DIURESIS.

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A. Solute diuresis, in contrast to water diuresis, can be caused by the presence in the filtrate of solutes in large excess of the amount the tubule can reabsorb or by the inhibition of specific reabsorptive mechanisms. In either situation water reabsorption is inhibited and this reduces the reabsorption of many other solutes. Urine volume rises and the osmotic concentration of the urine declines toward the plasma level. In most situations, reabsorption of fluid in the proximal tubule is affected and increases flow of tubular fluid into the rest of the nephron. If there is no direct effect on distal nephron mechanisms, salt and water reabsorption in that section will increase. However, this is limited and salt and water excretion will also increase. If the effectiveness of the countercurrent system is impaired by a very high rate of delivery from the proximal tubule, water excretion will increase further. In some instances distal sections of the nephron are also primarily affected.

B. Because of the high water permeability and high conductance of the proximal tubular epithelium, the tubular fluid electrolyte and osmotic concentrations can deviate only slightly from that of the interstitial fluid. Water can be reabsorbed only when solute is reabsorbed and the two must be reabsorbed in about the same proportion as they exist in the filtrate, that is, the reabsorbed fluid must be practically isosmotic. Any reduction in solute reabsorption produces an equivalent inhibition of water reabsorption. The chief osmotic solutes in the filtrate are Na and its attendant anions. These are reabsorbed by mechanisms that are severely gradient-limited because of the high conductance of the epithelium. Any inhibition of water reabsorption quickly results in a small gradient that drastically limits the net reabsorption of these ions. Because of this close interrelationship between salt and water transport, the reabsorption of both can be blocked by inhibiting the reabsorption of either.

C. Water reabsorption in the proximal tubule will be inhibited whenever there is an accumulation of poorly reabsorbed solute in the lumen. Normally, there is a small fraction of the solute present in the glomerular filtrate that is poorly reabsorbed by the proximal tubule. As the reabsorption of the other solutes and water proceeds, the concentration of these poorly absorbed solutes in the tubular fluid increases. Since the total solute concentration must always remain the same, reabsorption will continue only to the extent that the concentration of other solutes can be reduced. The proximal tubule can do this to a limited extent. For example, the concentration of glucose in the tubular fluid is reduced essentially to zero. However, the concentration of the major osmotic solutes in the tubular fluid can be reduced only slightly. Therefore, as the reabsorption of fluid raises the concentration of poorly absorbed solute in the filtrate, a point is reached at which the Na and anion concentration must be reduced if the total osmotic concentration of the tubular fluid is to be maintained constant and water reabsorption is to proceed. Since the Na and anion concentrations can be reduced only slightly, water and salt reabsorption are halted soon after that point is reached. If the poorly absorbed solute concentration in the filtrate is raised, the amount of water that can be reabsorbed, before that limiting point is reached, is reduced.

Table 7-1 shows the normal situation (I) and an example of what occurs when the poorly absorbed solute concentration of the filtrate is raised (II). In the first case 70% of the filtered water and salt is reabsorbed; in the example of the second case the limiting point is reached when only 50% of the filtrate is reabsorbed. Urea is one solute that can cause primary inhibition of water reabsorption in the proximal tubule. Urea is reabsorbed to some extent by the proximal tubule, but its concentration does rise in the tubular fluid as water is reabsorbed. This rise in concentration must be balanced by a fall in the concentration of some other solute if the total solute concentration is to remain constant and water reabsorption is to continue. A rise in the plasma concentration of urea, such as may occur in a person on a high protein diet, will cause a mild solute diuresis. Mannitol, a monosaccharide resembling glucose, is often used to produce solute or osmotic diuresis. Mannitol is not metabolized by the body and is poorly reabsorbed by the nephron. It is much more effective than urea in causing diuresis because the tubule is much less permeable to it. Glucose also causes solute diuresis when it is present in the glomerular filtrate in a quantity that exceeds the T_m of the glucose transport mechanism. This may occur in uncontrolled diabetes mellitus.

D. If any of the solute reabsorptive mechanisms in the proximal tubule are inhibited, that solute in effect becomes a poorly reabsorbed solute and inhibits the reabsorption of water. That in turn inhibits the other gradient-limited solute transport mechanisms and the same type of solute diuresis ensues. For instance, acetazolamide inhibits bicarbonate reabsorption, particularly in the proximal tubule. The drop in anion reabsorption retards Na reabsorption and both changes secondarily block water reabsorption.

E. The distal sections of the nephron may compensate to some extent for inhibition of reabsorption in the proximal tubule. A rise in GFR or inhibition of proximal tubular reabsorption increases the volume flow into the distal sections of the nephron. The effect of an increase in flow rate on the gradient-limited salt reabsorptive mechanisms results in an increase in the reabsorption of salt. This effect is illustrated in Fig. 7-9A. A small section of a hypothetical tubule is immersed in a bath of infinite volume with a Na concentration of 150 mM. The tubule is relatively impermeable to water and possesses an active transport system for Na. It also has a moderate sodium conductance or permeability. As fluid flows through the tubule, the active transport system reduces the Na concentration in the tubular fluid. As that concentration falls along the length of the tubule to 60 mM, the rate of passive back-flux of Na into the tubule increases and near the end of the section rises to equal the rate of active transport out. At that point no further net reabsorption of Na occurs. 90 moles of Na are reabsorbed per minute before that point is reached. If the flow rate through the tubule is increased as in Fig. 7-9B, the amount of Na flowing through the tubule/min doubles and the same rate of active transport out does not reduce the concentration of Na to the same extent. This keeps the rate of passive influx below the rate of the active outflux, and thus the net rate of reabsorption increases from 90 to 120 moles/min. Note also that this increased net reabsorptive rate does not keep up with the delivery rate and the amount exiting the tubule also rises from 60 to 180 mmoles/min.

When the flow rate through the loop of Henle rises, the gradient effect permits the thick ascending limb to increase solute transport into the medullary ISF as described above. This also occurs to a lesser extent in the distal tubule and collecting tubule. Thus, inhibition of salt reabsorption in the proximal tubule is partly counteracted by increased reabsorption in the distal structures. This is not complete, however, and the amount of salt excreted increases.

Fig. 7-9. An illustration of the effect of an increase to flow on net Na reabsorption.

There is also an effect on water reabsorption in the collecting tubule. The increase in flow rate will result in an increase in water reabsorption into the medullary ISF but again that is incomplete and water excretion also increases. In addition, the increase in water reabsorbed into the medullary ISF begins to limit the effectiveness of the countercurrent system and the osmotic concentration if the urine will begin to drop toward isotonicity. In extreme situations, the volume flow through the loop of Henle and the collecting tubule can be large enough to wash out the countercurrent gradient and the osmotic concentration of the urine begins to resemble that of the glomerular filtrate.

F. Solute reabsorption in the distal nephron may also be inhibited, causing solute diuresis . Primary inhibition of salt reabsorption in the ascending limb of Henle's loop can be caused by the "loop" diuretics, the most potent diuretic agents available. Among these are furosemide, bumetanide and ethacrynic acid. Inhibition of the Na-2Cl-K cotransporter blocks the primary engine of the countercurrent mechanism, inhibiting salt delivery to the medullary interstitial fluid. This results in inhibition of water reabsorption in the distal tubule and in the collecting tubule. Salt and water excretion increase and the osmotic concentration falls toward the plasma level. Salt transport in the distal tubule can be inhibited by the thiazide diuretics. This also increases salt and water excretion and reduces urine osmolality toward the plasma level.

QUESTIONS:  
12. Why are the processes of Na, Cl, HCO₃ and water absorption by the proximal tubule so highly interdependent? Why does inhibition of Na reabsorption interfere with the reabsorption of Cl, HCO₃, and water? Why does inhibition of water reabsorption interfere with reabsorption of Na, HCO₃, and Cl?

13. How does a rise in the delivery of fluid to the thick ascending limb result in an increase in the amount of salt reabsorbed by that structure? How does a modest increase in the delivery of fluid to the collecting duct increase the rate of water reabsorption by that structure? What is the effect of a large increase in the delivery of fluid to that section of the nephron?

14. The following data were obtained in an experiment on a dog weighing 13.2 kg. The ureter of one kidney was catheterized and isotonic saline was infused I.V. at a slow rate to induce a modest diuresis so that a sufficient volume of urine could be collected for analysis. Then, following a control clearance period, mannitol was infused.

a. Calculate the rates of excretion of sodium and total solute.

b. What osmotic and volume changes were produced in each of the three body water compartments by the infusion of mannitol? (Mannitol is a 6-carbon monosaccharide, M.W. = 182. Cell membranes are impermeable to it.)

c. Why did P_Na and the hematocrit decline?

d. How and why did the reabsorption of salt and water in the proximal tubule change?

e. How did this affect the rest of the nephron?

f. Why did the osmotic concentration of the urine decline?

g. Is it possible that the rate of ADH secretion was altered? If so, how did the change affect the urine composition?

AN EARLY DESCRIPTION OF EXTREME OSMOTIC DIURESIS

The Extant Works of Aretaeus, the Cappadocian. Edited and translated by Francis Adams, London, Sydenham Society, 1856, p. 338

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