Dilution & concentration of urine

From Iusmphysiology

• started here on 03/25/11.

Contents 1 Dilution and concentration of urine 1.1 Why concentrate the urine? 1.2 Hydration state calculations 1.3 The long and short of Henle loops 1.4 Steep gradient of interstitial osmolarity 1.5 Kidney medulla contains two countercurrent mechanisms 1.6 Loop of Henle and countercurrent multiplication 1.7 Vasa recta and countercurrent exchange 1.8 Thermal models and countercurrent exchange 1.9 The collecting duct and the interstitial osmolarity 1.10 Nephron geography and reabsorption 1.11 Urea and the concentration of urine 1.12 Urea and NaCl are the osmotic solutes 1.13 Blood flow characteristics of the vasa recta 1.14 Factors that affect urine concentrating ability

[edit] Dilution and concentration of urine

[edit] Why concentrate the urine?

• The kidneys concentrate the urine in order to save water for the body.
• About 600 mOsm of solute is secreted per day.
  • If this were secreted at plasma concentrations, we would secrete 2 liters of water.
  • When concentrated maximally, we can secrete this much solute in 0.5 liters of water.
  • So we save 1.5 liters of water / day by concentrating the urine.

[edit] Hydration state calculations

• In considering the hydration state we care about how concentrated the urine is relative to the plasma and how much urine is being produced.

• The ratio of osmols in the urine to the plasma tells us whether more solute or more water is being lost:
  • U_osm / P_osm describes how concentrated the urine is relative to the plasma.
    • The closer to infinite the ratio approaches, the more concentrated and the more water is conserved.
    • The closer to zero the ratio approaches, the less concentrated and the more water is lost.
  • Concentration of the urine is expressed in osmols: U_osm
  • Concentration of the plasma is expressed in osmols, also: P_osm
  • When U_osm / P_osm > 1, solute is being lost from the blood relative to water.
    • When Uosm > Posm, we call the urine hyperosmotic; that is, water would rush out of a cell if placed in this urine.
  • When U_osm / P_osm = 1, solute and water are being lost from the blood at equivalent rates.
    • In this case, we call the urine iso-osmotic to the plasma.
  • When U_osm / P_osm < 1, water is being lost from the blood relative to solute.
    • When Uosm < Posm, we call the urine hypo-osmotic; that is, water would rush into a cell placed in this urine.

• The next term of interest is C_osm, that is, the clearance of osmols.
  • Given our ratio of urine and plasma concentrations (U_osm / P_osm), we can develop a term that describes the net clearance of osmols by multiplying the ratio by the flow rate.
    • Recall that V-dot represents the urine flow rate.
  • C_osm = (U_osm / P_osm) * V
  • C_osm describes how much solute is being excreted as a function of flow rate (V), the concentration of the urine (U_osm) and the concentration of the plasma (P_osm).
    • In another sense, C_osm describes how much solute is being excreted as a function of flow rate (V) and water retention / loss (U_osm / P_osm).
  • C_osm is directly related to flow rate: as flow increases or decreases, solute excretion increases or decreases.
  • C_osm can also be elevated by increasing the concentration of the urine or decreasing the concentration of the plasma.
    • This makes sense because more concentrated urine contains relatively more solute than less concentrated urine, so it will clear solutes from the plasma more rapidly (that is, result in an elevated C_osm).
    • Note that the concentration of the plasma does not change often.

• A mis-named term called the "free water clearance" describes how much water is removed from the plasma to generate urine; that is, free water clearance can be used to determine if a patient is over- or under-hydrated.
  • "Free water clearance" is denoted as C_H20.
  • "Free water clearance" is a misnomer because this does not really describe the "clearance" of water (as in the "clearance of aspirin").
  • C_H20 = V - C_osm = V - (V * (U_osm / P_osm)) = V * (1 - (U_osm / P_osm))
    • Note that we are subtracting a portion of the flow from the flow itself.
  • We know that the ratio of Uosm to Posm describes the clearance of osmols in terms of flow.
  • So, to subtract the clearance of osmols from the flow gives us a term describing how much water was not cleared.
    • That is, C_H20 describes how much of the plasma was cleared of solute.
    • When C_H20 > 0, solute-free water is being removed from the plasma in order to dilute the urine.
    • When C_H20 < 0, solute-free water is being removed from the urine in order to concentrate the urine.
    • When C_H20 = 0, the urine is iso-osmotic relative to the plasma.

[edit] The long and short of Henle loops

• Species with a high proportion of long loops of henle (relative to short loops) can achieve greater urine concentration.
  • Recall that long loops of henle drop deep into the medulla whereas short loops only superficially enter the medulla.
• 15% of human loops are long.
• The kangaroo rat rarely has to drink water because it has many long loops and can conserve so much of its water.

• The ability to produce osmotically concentrated urine is directly proportional to the length of the Henle loops.
  • Desert dwellers have long loops, hydrated habitators have short loops.

[edit] Steep gradient of interstitial osmolarity

• The cortex has an interstitial osmolality of about 300 mOsm while the inner medulla osmolality is 1200 mOsm.
  • This was determined from frozen rat sections of kidneys.

[edit] Kidney medulla contains two countercurrent mechanisms

• Recall that the whole point of the osmolarity gradient along the nephron is to allow water to flow down an osmolarity gradient across the collecting duct.
• So, the first thing to remember is that water only flows across the collecting duct when AVP is being expressed otherwise the collecting duct is impermeable to water.
• To understand the countercurrent mechanisms, remember that the kidney is trying to make the medulla highly filled with solute and very low on water (that is, the medulla should have a high osmolarity) so that water can flow from the filtrate (which is pretty concentrated at the collecting duct, into the medulla).
• Now, understand that the loop of henle establishes the osmolarity gradient and the vasa recta maintain the gradient.
  • We say that the loop of henle is a countercurrent multiplier. That is, it puts solute into the medulla.
  • We say that the vasa recta is a countercurrent exchanger. That is, it takes water out of the medulla.

[edit] Loop of Henle and countercurrent multiplication

• Recall that the whole point of the loop of Henle is to increase solute levels of the medulla.
• The loop achieves a high solute, low water distribution by alternating (along the descending and ascending loops) whether or not water or NaCl can escape the filtrate into the interstitium.
  • As filtrate descends, water can escape into the interstitium but NaCl cannot follow.
    • Note that this escape of water might seem to balance the pumping out of NaCl, but it will be removed from the medulla by the vasa recta.
  • As filtrate ascends, NaCl is actively pumped into the interstitium but water cannot follow.
• It is important to understand that NaCl is actively pumped; it is this burning of ATP that allows us to generate a gradient.
  • Recall that without energy, nothing flows against its gradient.
  • This active pumping is able to generate a gradient of 200 mOsm / kg between the descending and ascending filtrate; one can imagine that there is a limit to the gradient this pump can generate because of leaky channels, ATP turnover, et cetera.
• We call this a multiplication countercurrent because as the filtrate moves down and back up the tubule, the gradient is continually brought to a 200 mOsm difference such that the difference along the axis of the loop of Henle increases.
• In the loop of Henle, relatively more NaCl is pumped out (on the way up) than water is gained (on the way down) (that is the filtrate becomes more dilute), so the loop is often called the diluting segment of the nephron.

[edit] Vasa recta and countercurrent exchange

• Recall that the whole point of the vasa recta is to decrease the water levels of the medulla.
• Vasa recta are long, thin capillaries from the efferent arterioles of the juxtamedullary glomeruli.
• Recall that the loop of Henle let water enter the medulla through passive reabsorption in the descending loop.
• The vasa recta are the mechanism by which this water is removed from the medulla, resulting in a net gain of solute to the interstitial fluid (given all that is occurring at along the loop of Henle and the vasa recta).
• The vasa recta allow water to short circuit the path of the blood; that is, water will move from the descending branch of the vasa recta to the ascending.
  • Water can short circuit the vasa recta loop because solutes (namely NaCl and urea) can also short circuit in the opposite direction.
  • NaCl and urea that short circuit are said to be "cycling" because they can flow through the same stretch of vasa recta multiple times.

• Note that if the vasa recta blood flow rate is greatly increased, it can "wash out" the solutes from the medulla.
  • That is, high blood flow rates can cause lots of solute reabsorption in from the medulla and decrease the osmolarity gradient along the cortical-medullary axis.
  • This would result in a decreased ability to concentrate the urine and a decreased ability to shed water via urine.

So, if saline is given to increase the extracellular compartment and too much is given too fast, then the pt can't shed the excess via urine (because they can't concentrate urine), so then will edema and such result?  Does edema only result after this point of flushing out the solute or can edema result before that?

[edit] Thermal models and countercurrent exchange

• Thermal models can help demonstrate how countercurrent exchange works.
• Imagine a source of heat at the bottom of the medulla:
  • As filtrate flows down the descending limb to the source of heat it will heat up.
  • As filtrate flows up the ascending limb (right next to the descending limb) it will heat the descending fluid next to it.
  • Since the fluid now flowing down the descending limb is being heated by the ascending fluid and by the heat source itself (through conduction), there will be an increased temperature of that fluid when it hits the bottom.
  • An equilibrium will be reached.
  • There will be a nice heat gradient in the descending and ascending fluid as they flow along the cortical-medulla axis.
    • And this gradient will generate a larger difference (larger gradient) than if one had just stuck a heat source at the bottom of the medulla and had no fluid flow.

[edit] The collecting duct and the interstitial osmolarity

• Now that the countercurrent mechanisms have set up this awesome osmolarity gradient, the collecting duct (which passes through the entire distance of the medulla) has an excellent opportunity to concentrate the urine.
  • Recall that the collecting duct can only concentrate the urine via the countercurrent-generated osmolarity gradient when ADH is present.
  • Without ADH, there is no aquaporin2 on the apical surface (lumen-facing surface) of the collecting duct principal cells and therefore no water flow from the filtrate to the interstitium.
  • However, when ADH is present, AQ2 is present and water can flow down the osmolarity gradient (that is, the water concentration gradient) from the filtrate to the interstitium.
• When ADH is present, water flows from the filtrate, through AQ2, AQ3/4, into the interstitium, and then into the blood found in the vasa recta.
• When ADH is present, urine reaches the same concentration as the interstitial fluid at the papilla of the medulla.
  • Urine concentration reaches about 1200 mOsm.

• There is decreased osmolarity gradient without ADH for several reasons:
  • There is a small amount of water reabsorption even without ADH.
  • There is a small amount of urea flow from filtrate to medulla even without ADH.
  • There is increased medullary blood flow via vasa recta.

[edit] Nephron geography and reabsorption

• At the glomerulus, 100% of the initial filtrate is in the tubule.
• At the PCT, 30% of the initial filtrate remains in the tubule.
• At the DCT, 15-20% of the initial filtrate remains in the tubule.
• The amount of filtrate remaining in the collecting duct depends on the presence or absence of AVP:
  • Without AVP, the collecting duct does not retain any water so 15-20% of the initial filtrate remains in the tubule (just like we saw in the DCT).
  • With AVP, at the end of the collecting duct, 1% of the initial filtrate remains in the tubule.

[edit] Urea and the concentration of urine

• Recall that when ADH is present, the body is trying to reabsorb all the water it can.
• One effect of ADH on the collecting duct is to make the very medullary tip of the collecting duct permeable to urea (that is, urea can flow from the filtrate to the interstitium by chemical gradient).
  • Urea movement from filtrate into medullary interstitial space is facilitated by specific urea transporters.
• As urea moves from the filtrate to the interstitium by chemical gradient it increases the osmolarity of the interstitium, thus drawing water with it.
  • The water is then cleared from the medullary interstitium by the vasa recta.
  • The urea ends up back in the filtrate and in the blood by way of vasa recta absorption and loop of Henle secretion.
• All this to say that urea is required for efficient urine concentration!

[edit] Urea and NaCl are the osmotic solutes

• So, urea in the medullary interstitium balances the urea in the collecting duct filtrate.
  • Urea movement is facilitated but not active, so they can only balance one another.
• So, the NaCl that has been concentrated in the interstitium must provide enough osmotic force to counterbalance the osmotic pull of all the other solutes in the filtrate of the collecting duct.
• So the osmotic pull of urea and NaCl in the interstitium pull water from the collecting duct filtrate when everything is going well.

• Note that it is as of yet of unclear how NaCl is concentrated in the medullary interstitium given the fact that NaCl is passively reabsorbed at the ascending limb of the loop of Henle.

I thought that this occurred b/c of the active pumping of NaCl out of the filtrate into the interstitium at the ascending loop.

• The osmotic gradient and low blood flow make the intermedullary space a very hostile environment for cells.

[edit] Blood flow characteristics of the vasa recta

• Recall that the vasa recta is responsible for absorbing the water reabsorbed by the collecting duct upon ADH signaling.
• Recall that the descending loop of Henle lets water flow out of the filtrate.
• These two sources of water cause vasa recta outflow to be higher than vasa recta inflow.
• One can also describe this as a mass action balance: the osmolality of filtrate is decreasing along the way so the water has to go somewhere and it is going into the vasa recta; therefore the vasa recta's osmolality must be increasing (and thus flow must increase).
• Similarly, the filtrate flow will be decreasing as its osmolality decreases.

[edit] Factors that affect urine concentrating ability

• ADH: more ADH, more AQ2, more H20 reabsorption, more concentrated urine.
• NaCl at ascending limb of loop of Henle

**The more NaCl makes it to the ascending limb of the loop of Henle, ...
Is NaCl the limiting factor in how much gradient can be generated between the ascending and descending loops by active NaCl secretion at the ascending loop?

• Reabsorption of NaCl by the ascending loop

**The more NaCl that is reabsorbed, the less osmolarity gradient there is and the less water is reabsorbed at the collecting duct.

• Delivery of fluid to medullary collecting ducts

**There is some threshold at which the collecting duct cannot reabsorb all the water passing through, even under ADH stimulation.

• Medulary blood flow
  • If medullary blood flow is limited, water reabsorption from the interstitium by the vasa recta will be limited.
• Urea
  • If urea is not available, less osmolarity gradient will be generated between the collecting duct filtrate and the medullary interstitium so less water will be reabsorbed.
• Length of Henle's loo
  • The longer the loop, the greater the gradient can be formed along the cortical-medullary axis and the more water can be reabsorbed at the collecting duct.
• Aging
  • As one ages, nephrons become less in number and less effective.
• Neurogenics diabetes insipidus
  • Recall that neurogenic DI is caused by an under-expression of ADH.
  • Decreased ADH means decreased AQ2, decreased water reabsorption, and dilute urine.
  • We give exogenous ADH to treat neurogenic (central) diabetes insipidous.
• Nephrogenic diabetes insipidous
  • Recall that nephrogenic DI is caused by a diminished response to ADH at the collecting duct.
    • Most likely due to a disfunctional V2 receptor or AQ2 channel.
  • We use thiazide diuretics and low Na diet to control volume and decrease GFR.
    • Recall that thiazides inhibit the Na / Cl cotransporter at the DCT.
• Primary polydipsia
  • Primary polydipsia is the suppression of ADH by excessive fluid intake.
  • This makes sense because if you drink lots of water, the body will decrease ADH to lose some of the water by urine.

• Both primary polydipsia (drinking lots of water) and nephrogenic diabetes insipidous will present as high urine production.
  • How do you tell the difference between primary polydipsia and nephrogenic diabetes insipidous?
  • One way is to take away water from the patient.
  • A nephrogenic DI patient without water will continue to make dilute urine and will become dehydrated.
  • A patient suffering from primary polydipsia will generate enough dilute urine to bring the body back to homeostatic water balance and then return to normal ADH expression and normal production of concentrated urine.

• stopped here on 03/25/11.