Urine concentration

By:
Hossam Alkashgari, MBBS, MS, PhD
Physiology Department
Renal Module
Objectives
• To understand the physiological mechanisms that regulate urine
concentration.
• Describe the corticopapillary osmotic gradient and how it is
established and maintained.
• Describe the mechanisms of urine concentration.
• Describe the mechanisms of diluting urine.
• Understand the different types of diuresis.
Regulation of plasma osmolarity
• is accomplished by varying the amount of water excreted relative to
the amount of solute excreted (i.e., by varying urine osmolarity).
1. Response to water deprivation
2. Response to water intake
 Corticopapillary osmotic gradient
• Is the gradient of osmolarity from the cortex (300 mOsm/L) to the
papilla (1200 mOsm/L) and is composed primarily of NaCl and
urea.
• Is established by countercurrent multiplication and urea
recycling.
• Is maintained by countercurrent exchange in the vasa recta.
The loop of Henle in relation to the cortex and
medulla
 Urine concentration mechanisms
1. Countercurrent multiplication in the loop of Henle
• Depends on NaCl reabsorption in the thick ascending limb and countercurrent flow in the
descending and ascending limbs of the loop of Henle.
• Is augmented by ADH, which stimulates NaCl reabsorption in the thick ascending limb.
Therefore, the presence of ADH increases the size of the corticopapillary osmotic gradient.
2. Urea recycling from the inner medullary collecting ducts into the medullary
interstitial fluid also is augmented by ADH (by stimulating the UT1 transporter).
3. Vasa recta are the capillaries that supply the loop of Henle. They maintain the
corticopapillary gradient by serving as osmotic exchangers. Vasa recta blood
equilibrates osmotically with the interstitial fluid of the medulla and papilla.
Countercurrent multiplication in the loop of Henle
 Countercurrent multiplication in the loop of Henle
(summary)
Step 1: First, assume that the loop of Henle is filled with fluid with a concentration of 300 mOsm/L, the same as that leaving the proximal
tubule.

Step 2: Active absorption of NaCl by thick ascending limb on the loop of Henle, establishes a 200-mOsm/L concentration gradient between
the tubular fluid (200 mOsm/L) and the interstitial fluid (400 mOsm/L). This 200 mOsm/L is the maximum gradient that can be established by
TAL.
Step 3: Absorption of water (Osmosis) in the descending limb of the loop of Henle established an osmotic equilibrium (400 mOsm/L) between
descending limb of the loop of Henle and interstitium.
Step 4: Additional flow of fluid into the loop of Henle from the proximal tubule (300 mOsm/L), which causes the hyperosmotic fluid previously
formed in the descending limb (400 mOsm/L) to flow into the ascending limb.
Step 5: Additional ions are pumped into the interstitium, until a 200 mOsm/L osmotic gradient is established, with the interstitial fluid
osmolarity rising to 500 mOsm/L.
Step 6: Then, once again, the fluid in the descending limb reaches equilibrium with the hyperosmotic medullary interstitial fluid due to water
absorption in descending limb of the loop of Henle.
Step 7: These steps are repeated over and over, with the net effect of adding more and more solute to the medulla in excess of water; with
sufficient time, this process gradually traps solutes in the medulla and multiplies the concentration gradient established by the active pumping
of ions out of the thick ascending loop of Henle, eventually raising the interstitial fluid osmolarity to 1200 to 1400 mOsm/L.
Countercurrent multiplication in the loop of Henle
• First, assume that the loop of Henle is filled with fluid with a concentration
of 300 mOsm/L, the same as that leaving the proximal tubule (step 1).
• Next, the active pump of the thick ascending limb on the loop of Henle is
turned on, reducing the concentration inside the tubule and raising the
interstitial concentration; this pump establishes a 200-mOsm/L
concentration gradient between the tubular fluid and the interstitial fluid
(step 2). The limit to the gradient is about 200 mOsm/L because
paracellular diffusion of ions back into the tubule eventually
counterbalances transport of ions out of the lumen when the 200-mOsm/L
concentration gradient is achieved.
Countercurrent multiplication in the loop of Henle

• Step 3 is that the tubular fluid in the descending limb of the loop of
Henle and the interstitial fluid quickly reach osmotic equilibrium
because of osmosis of water out of the descending limb. The
interstitial osmolarity is maintained at 400 mOsm/L because of
continued transport of ions out of the thick ascending loop of Henle.
Thus, by itself, the active transport of sodium chloride out of the thick
ascending limb is capable of establishing only a 200-mOsm/L
concentration gradient, much less than that achieved by the
countercurrent system.
Countercurrent multiplication in the loop of Henle

• Step 4 is additional flow of fluid into the loop of Henle from the
proximal tubule, which causes the hyperosmotic fluid previously
formed in the descending limb to flow into the ascending limb. Once
this fluid is in the ascending limb, additional ions are pumped into the
interstitium, with water remaining behind, until a 200-mOsm/L
osmotic gradient is established, with the interstitial fluid osmolarity
rising to 500 mOsm/L (step 5)
Countercurrent multiplication in the loop of Henle
• Then, once again, the fluid in the descending limb reaches equilibrium with the hyperosmotic
medullary interstitial fluid (step 6), and as the hyperosmotic tubular fluid from the descending
limb of the loop of Henle flows into the ascending limb, still more solute is continuously pumped
out of the tubules and deposited into the medullary interstitium.
• These steps are repeated over and over, with the net effect of adding more and more solute to
the medulla in excess of water; with sufficient time, this process gradually traps solutes in the
medulla and multiplies the concentration gradient established by the active pumping of ions out
of the thick ascending loop of Henle, eventually raising the interstitial fluid osmolarity to 1200 to
1400 mOsm/L as shown in step 7.
• Thus, the repetitive reabsorption of sodium chloride by the thick ascending loop of Henle and
continued inflow of new sodium chloride from the proximal tubule into the loop of Henle is called
the countercurrent multiplier. The sodium chloride reabsorbed from the ascending loop of Henle
keeps adding to the newly arrived sodium chloride, thus “multiplying” its concentration in the
medullary interstitium.
Urea recycling
• Urea is reabsorbed and secreted in the nephron by diffusion, either
simple or facilitated, depending on the segment of the nephron.

• Fifty percent (50%) of the filtered urea is reabsorbed in the proximal

tubule by simple diffusion.

• The distal tubule, cortical collecting ducts, and outer medullary

collecting ducts are impermeable to urea; thus, no urea is reabsorbed
by these segments.

• Urea is secreted into the thin descending limb of the loop of Henle by
simple diffusion (from the high concentration of urea in the medullary
interstitial fluid).

• ADH stimulates a facilitated diffusion transporter for urea (UT1) in the

inner medullary collecting ducts. Urea reabsorption from inner
medullary collecting ducts contributes to urea recycling in the inner
medulla and to the addition of urea to the corticopapillary osmotic
gradient.

• Urea excretion varies with urine flow rate. At high levels of water
reabsorption (low urine flow rate), there is greater urea reabsorption
and decreased urea excretion. At low levels of water reabsorption
(high urine flow rate), there is less urea reabsorption and increased Urea recycling
urea excretion.
 Urea recycling
• Urea diffuses into the thin loop of Henle, and then
passes through the distal tubules, and finally passes
back into the collecting duct.

• The recirculation of urea helps to trap urea in the

renal medulla and contributes to the
hyperosmolarity of the renal medulla.

• The heavy dark lines, from the thick ascending loop

of Henle to the medullary collecting ducts, indicate
that these segments are not very permeable to urea.

• Numerical values are in milliosmoles per liter of urea

during antidiuresis, when large amounts of
antidiuretic hormone are present. Percentages of
the filtered load of urea that remain in the tubules
are indicated in the boxes.
Vasa recta countercurrent exchange
Plasma flowing down the descending limb of
the vasa recta becomes more hyperosmotic
because of diffusion of water out of the blood
and diffusion of solutes from the renal
interstitial fluid into the blood.
In the ascending limb of the vasa recta,
solutes diffuse back into the interstitial fluid
and water diffuses back into the vasa recta.
Large amounts of solutes would be lost from
the renal medulla without the U shape of the
vasa recta capillaries.

Countercurrent exchange in the vasa recta

Notes:
• Once the interstitial osmotic gradient is established by the counter
current multiplier, it is maintained by the counter current exchange
mechanism of the vasa recta.
• The counter current multiplier mechanism is active whereas the
counter current exchange mechanism is passive.
Production of concentrated urine
• Is also called hyperosmotic urine, in which urine osmolarity > blood
osmolarity.
• Is produced when circulating ADH levels are high (e.g., water
deprivation, volume depletion, SIADH).
Production of concentrated urine
1. Corticopapillary osmotic gradient—high ADH
• is the gradient of osmolarity from the cortex (300 mOsm/L) to the
papilla (1200 mOsm/L) and is composed primarily of NaCl and
urea.
2. Proximal tubule—high ADH
• The osmolarity of the glomerular filtrate is identical to that of plasma (300
mOsm/L).
• Two-thirds of the filtered H2O is reabsorbed isosmotically (with Na+, Cl-,
HCO3-, glucose, amino acids, and so forth) in the proximal tubule
Production of concentrated urine
3. Thick ascending limb of the loop of Henle—high ADH
• is called the diluting segment.
• reabsorbs NaCl by the Na+–K+–2Cl- cotransporter.
• is impermeable to H2O. Therefore, H2O is not reabsorbed with NaCl, and the
tubular fluid becomes dilute.

4. Early distal tubule—high ADH

• is called the cortical diluting segment.
• Like the thick ascending limb, the early distal tubule reabsorbs NaCl but is
impermeable to water. Consequently, tubular fluid is further diluted.
Production of concentrated urine
5. Late distal tubule—high ADH
• ADH increases the H2O permeability of the principal cells of the late distal tubule.
• H2O is reabsorbed from the tubule until the osmolarity of distal tubular fluid equals that of the surrounding
interstitial fluid in the renal cortex (300 mOsm/L).
6. Collecting ducts—high ADH
• As in the late distal tubule, ADH increases the H2O permeability of the principal cells of the collecting ducts.
• As tubular fluid flows through the collecting ducts, it passes through the corticopapillary gradient (regions of
increasingly higher osmolarity), which was previously established by countercurrent multiplication and urea
recycling.
• H2O is reabsorbed from the collecting ducts until the osmolarity of tubular fluid equals that of the
surrounding interstitial fluid.
• The osmolarity of the final urine equals that at the bend of the loop of Henle and the tip of the papilla (1200
mOsm/L).
Production of dilute urine
• Is called hyposmotic urine, in which urine osmolarity < blood
osmolarity.
• Is produced when circulating levels of ADH are low (e.g., water intake,
central diabetes insipidus) or when ADH is ineffective (nephrogenic
diabetes insipidus)
Production of dilute urine
1. Corticopapillary osmotic gradient—no ADH
• is smaller than in the presence of ADH because ADH stimulates both
countercurrent multiplication and urea recycling.
2. Proximal tubule—no ADH
• As in the presence of ADH, two-thirds of the filtered water is reabsorbed
isosmotically
3. Thick ascending limb of the loop of Henle—no ADH
• As in the presence of ADH, NaCl is reabsorbed without water, and the tubular
fluid becomes dilute (although not quite as dilute as in the presence of ADH).
Production of dilute urine
4. Early distal tubule—no ADH
• As in the presence of ADH, NaCl is reabsorbed without H2O and the tubular
fluid is further diluted.
5. Late distal tubule and collecting ducts—no ADH
• In the absence of ADH, the cells of the late distal tubule and collecting ducts
are impermeable to H2O.
• Thus, even though the tubular fluid flows through the corticopapillary
osmotic gradient, osmotic equilibration does not occur.
• The osmolarity of the final urine will be dilute with an osmolarity as low as 50
mOsm/L.
 Diuresis
• 1. Osmotic diuresis:
• This occurs when there is an increase in solutes in the urine, such as glucose or
mannitol, which draws water out of the body's tissues and increases urine
production.
• 2. Pressure diuresis:
• This occurs when there is an increase in blood pressure, which increases the pressure
within the glomerulus of the kidneys and increases urine production.
• 3. Hormonal diuresis:
• This occurs when hormones such as atrial natriuretic peptide (ANP) or aldosterone
increase urine production by regulating sodium and water reabsorption in the
kidneys.
• 4. Diuretics
Thank you!