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Concentration of Urine

Dr Raghuveer Choudhary Dept. of Physiology Dr. S.N.Medical College Jodhpur

Urea Handling
(1) PCT
About 50% of the filtered urea is passively reabsorbed The wall of PCT is partially permeable to urea but highly permeable to water so water reabsorption from PCT → increases urea concentration in tubular lumen. This creates concentration gradient

→ Urea reabsorption.

(2) Thick ascending limb of loop of Henle, DCT and cortical collecting tubules
All are relatively impermeable to urea. H2O reabsorbed in DCT and cortical collecting tubule (in presence of ADH)  increased urea concentration in tubular fluid.

(3) Inner medullary portion of the collecting duct
Urea diffuses into the medullary interstitium to increase its osmolality. Diffusion of urea is facilitated by ADH. 40 - 60% of the tubular load of urea is excreted in urine.

►Urea cycle

Urea moves from the medullary interstitium into the thin loop of • the Henle and back down into the medullary collecting • duct and again to medullary interstitium • several times before urea is excreted.

Urea recycling

URINE CONCENTRATION

PRODUCTION OF CONCENTRATED URINE
• Concentrated urine is also called hyperosmotic urine (urine osmolarity > blood osmolarity). • The kidney excretes excess solutes, but does not excrete excess amounts of water. • The basic requirements for forming a concentrated urine are: 1. a high level of ADH, e.g., in water deprivation or hemorrhage   permeability of late DCT & CDs to water, allowing these segments to reabsorb a large amount of water. 2. a high osmolarity of the renal medullary interstitial fluid  provides the osmotic gradient necessary for water reabsorption to occur in the presence of high levels of ADH. • After passing to the interstitium, water is carried by the vasa recta back into the blood.
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Reabsorption: Loop of Henle

PRODUCTION OF CONCENTRATED URINE
Reabsorption of Water in Presence of ADH:
In PCT, loop of Henle & early DCT: - Same as in formation of dilute urine (see before). - The tubular fluid reaching the late DCT is hyposmotic (100 mOsm/L). Late DCT: - ADH  the water permeability of the principal cells of the late DCT.  Water is reabsorbed until the osmolarity of the DCT equals that of surrounding interstitial fluid in renal cortex (300 mOsm/L). CDs: - ADH  the water permeability of principal cells of CDs. - As the tubular fluid flows through the CDs, it passes through regions of increasing hyperosmolarity toward the inner medulla. - Water is reabsorbed from the CDs until the osmolarity of the tubular fluid equals that of the surrounding interstitial fluid. 9  The osmolarity of the final urine reaches 1200 mOsm/L.

II. PRODUCTION OF CONCENTRATED URINE (cont.)

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II. PRODUCTION OF CONCENTRATED URINE (cont.)

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The Countercurrent System
• The countercurrent system is responsible for the creation & maintenance of a gradually increasing hyperosmolarity in the renal medullary interstitium, which is essential for enabling the kidney to concentrate urine in the presence of enough circulating ADH.
• This osmotic gradient is due to accumulation of solutes (primarily NaCl & urea) in great excess of water in the medullary interstitium. • Once the high solute concentration in medulla has been achieved, it is maintained by a balanced outflow of solutes & water in the medulla.
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The Countercurrent System
This osmotic gradient is 1. established by the loop of Henle, which acts as a countercurrent multiplier. 2. potentiated by the collecting duct, which allows urea recycling to occur. 3. maintained by the vasa recta, which act as countercurrent exchangers.

THE COUNTERCURRENT SYSTEM Loop of Henle Acting as Counter Current Multiplier

How does the renal medulla become hyperosmotic?
1. Before the osmotic gradient of the medulla is established, the osmolarity is the same throughout the nephron (300 mOsm/L). 2. The active pumping of NaCl out of the thick ascending limb occurs without concomitant movement of water   in osmolarity of tubular fluid inside ascending limb (200 mOsm/L) &  in osmolarity of medullary interstitial fluid (400 mOsm/L). 3. As fluid passes down the descending limb, it reaches osmotic equilibrium with medullary interstitium due to osmosis of water out of descending limb. [Interstitial osmolarity is maintained at 400 mOsm/L due to continued transport of ions out of thick ascending limb.] Thus, there is a gradual  in tubular fluid osmolarity as it flows towards the hairpin bend. 4. As more fluid enters descending limb from PCT, hyperosmotic fluid previously present in descending limb now flows into thick ascending limb.
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THE COUNTERCURRENT SYSTEM Loop of Henle Acting as Counter Current Multiplier
5. More NaCl is pumped from thick ascending limb into interstitium, but water remains in tubule. This continues until a 200 mOsm/L osmotic gradient is established. Now osmolarity in medullary interstitium has risen further to 500 mOsm/L. 6. Once again the fluid in descending limb equilibrates with hyperosmotic medullary interstitial fluid, now reaching 500 mOsm/L at the tip. 7. These steps are repeated over & over, adding more & more solute to the medulla in excess of water. This process gradually traps solutes in the medulla, eventually raising the interstitial osmolarity to 1200 mOsm/L. • Overall, the progressive transport of NaCl from the tubular fluid into the interstitium results in the establishment of a longitudinal osmotic gradient in the medulla.
 Thus, the countercurrent arrangement of the loop of Henle multiplies a relatively small transepithelial osmotic gradient into a large longitudinal 16 gradient.

COUNTERCURRENT MULTIPLIER SYSTEM IN LOOP OF HENLE

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Role of DCT & CDs in Urine Concentration
• Tubular fluid flowing from loop of Henle into DCT is dilute. • The early DCT further dilutes the fluid, because this segment, like the ascending limb of loop of Henle, actively transports NaCl out of tubule, but is impermeable to water.
• With high ADH concentrations, late DCT & cortical CD become highly permeable to water  large amounts of water are reabsorbed from the tubule into the cortical interstitium, where it is swept away by the peritubular capillaries. • With high ADH levels, there is further water reabsorption from medullary CDs to interstitium. However, the amount of water is relatively small compared with that added to the cortical interstitium. Reabsorbed water is quickly carried away by vasa recta into venous blood.

N.B. The fact that large amounts of water are reabsorbed into the cortex, rather than into the medulla, helps to preserve the high medullary interstitial fluid osmolarity. Thus, in the presence of ADH, the fluid at the end of CDs has the same osmolarity as the medullary interstitium (1200 mOsm/L).

 By reabsorbing as much water as possible, the kidneys form a highly concentrated urine while adding water back to ECF & compensating for deficit of body water.

Urea Recycling
• In the presence of ADH, urea contibutes 40% to the medullary interstitial osmolarity (= 500 mOsm/L) by passive urea reabsorption from the inner medullary CDs into the interstitium.

Mechanism: - Ascending limb of loop of Henle, DCT, cortical CDs & outer medullary CDs are impermeable to urea. - As water is reabsorbed from late DCT, cortical & outer medullary CDs, urea concentration  rapidly. - In inner medullary CDs, further water reabsorption takes place, so that urea concentration rises even more. Thus, urea diffuses out of the tubule into renal interstitium because this segment is highly permeable to urea, and ADH increases this permeability even more. - A moderate share of the urea that moves into medullary interstitium diffuses into thin descending limb of loop of Henle, so that it passes again in tubular fluid. It recirculates several times before it is excreted. Each time around it contributes to a higher concentration of urea in interstitium.  Urea recirculation provides an additional mechanism for forming a 20 hyperosmotic medulla.

UREA RECYCLING

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THE COUNTERCURRENT SYSTEM Vasa Recta as Countercurrent Exchanger
• Blood must be provided to renal medulla to supply its metabolic needs, but without a special blood flow system, solutes pumped into the medulla by countercurrent multiplier would rapidly get lost. • There are 2 special features in medullary blood flow that contribute to the preservation of the high solute concentrations: 1. The medullary blood flow is low (only 1-2% of total RBF)  sufficient for metabolic needs of tissues, but minimizes solute loss. 2. The vasa recta serve as countercurrent exchangers. Countercurrent Exchange Mechanism: • As blood descends into medulla, it becomes more & more concentrated, by gaining salt & losing water. At the tips of vasa recta blood has a concentration of 1200 mOsm/L. • As blood ascends back toward cortex, the reverse sequence occurs, and blood leaving vasa recta is only slightly hyperosmotic to normal plasma.  During its passage through medulla, blood has removed the excess salt & water that have been added by the transport processes occurring in the deeper regions of the medulla.  Thus, the U-shape of vasa recta maintains the concentration of solutes established by countercurrent system. 23

Vasa Recta as Countercurrent Exchanger

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Diuresis and diuretics
Diuresis is an increase in the rate of urine output. (A) H2O diuresis Increase H2O intake  decrease Osmotic. Pr  decrease ADH  decrease facultative H2O reabsorption i.e. Urine large volume and hypotonic. (B) Osmotic diuresis Unreabsorbable solute in PCT decrease obligatory H2O reabsorption  decrease Na+ concentration in tubular fluid  decrease osmolarity of medullary interstitium  decrease facultative H2O reabsorption.

-Urine: large volume and isotonic or hypertonic.
(C) Pressure diuresis Increase in arterial blood pressure leads to: •↑ GFR. •Inhibition of rennin angiotensin system → ↓ renin and angiotensin II production. •↑ Hydrostatic pressure in peritubular capillaries which → increase Na+ & H2O excretion.

(A)Thiazides:

(4) Diuretic drugs
inhibit Na reabsorption in DCT.

(B) Aldosterone inhibitors: (Potassium-sparing diuretics)
inhibit Na-K exchange in DCT and collecting tubules  decrease serum Na and increase serum K+.

e.g. alldactone:

(C) Carbonic anhydrase inhibitors e.g. acetazolamide
It inhibits carbonic anhydrase enzyme → decrease H secretion → decrease Na and HCO3- reabsorption in PCT and increase K secretion in DCT → increase Na, HCO3 & K excretion in urine. May lead to acidosis.

(Diamox).

(D) Loop diuretics e.g. frusemide (lasix):
inhibit Na-K-2Cl cotransporters in the thick ascending limb of loop of Henle.