Wednesday, April 17, 2013

Free water clearance

Hi everyone!
This is my attempt of explaining everything I know about free water clearance.. Hope you understand :)

What is free water clearance?
Free water clearance (CH2O) is the volume of blood plasma that is cleared of solute-free water per unit time.

What does it mean? @_@
Water follows salt everywhere it goes.
[Think of salt and water as a lovey dovey couple, in a very codependent relationship of course, water being the lead role xP ]

Suppose you had water going somewhere without salt :O
That water is free.
[Free of salt, the partner, probably on a break and being single for a while ;) ]

Normally, if you have to eliminate "x" amount of salt, you'll have to use up "y" amount of water to maintain an isosmotic condition.
[The stable relationship. Peace.]

Now, what if you had to eliminate the same "x" amount of salt by using "less than y" amount of water?
You'll use ADH, to conserve water.
[This is negative. Water is leaving salt behind in urine :( ]

Similarly, if you have "more than y" amount of water in your urine for "x" amount of salt excreted, you have produced a dilute urine.
This happens in the absence of ADH.
[This is positive. Water is so in love that it is going more than it should with salt in the urine <3 ]

So free water clearance tells you how much water you have to add/remove to make urine isoosmotic to plasma.
Positive free water clearance: It is the amount of water that is excreted in urine per minute in excess of what is necessary to make urine isosmotic with plasma.
Negative free water clearance: If the urine is more concentrated than the plasma, then free water is being extracted, giving a negative value for free water clearance.

Free Water (CH2O) = Total Urine - Water Occupied with Solute (Cosm) 
[Total urine water = Free water + Couple water :D ]

Also, Cosm = Urine osmolality x Urine flow / Plasma osmolality

Urine output = 0.6 L/day
Urine osmolality = 700 mOsmol/kg
Plasma osmolality = 230 mOsm/kg

CH2O = 0.6 - (0.6 x 700) / 230 = 0.6 - 1.8 = - 1.2
[Negative sign tells you that water left salt behind in urine, body has retained 1.2 liters of water.]

To sum it all up,
Negative free water clearance (concentrated urine) is seen with osmolarity of urine > 300 mOsm, when ADH is high and water is conserved, plasma osmolarity is decreased.

Positive free water clearance (dilute urine) is seen with osmolarity of urine < 300 mOsm, when ADH is low and free water is removed from body, plasma osmolarity is increased.

With ADH: CH2O < 0 (free water is retained)
Without ADH: CH2O > 0 (free water is excreted)

When is CH2O = 0?
Isotonic urine!

Doesn't that mean that the kidney has lost it's capacity to dilute or concentrate urine?
Yes! Free water clearance in chronic renal failure is zero.

What happens when you use loop diuretics?
Loop diuretics act on the thick ascending loop of Henle.
If you remember physiology, the loop of Henle generates a corticomedullary gradient by a counter current mechanism. A gradient of increasing osmolality along the medullary pyramids.
If you abolish this gradient by using a loop diuretic, you are as good as paralyzing the kidney's concentrating and diluting mechanism.
By abolishing the corticomedullary gradient, you block positive as well as negative free water clearance.
Free water clearance is zero.

Another example would be uncontrolled diabetes mellitus in which excess glucose enters the urine. Glucose is an osmotically active particle and it hinders the reabsorption of water from the loop of Henle.

This should also explain thiazides -
Thiazides act on the cortical diluting segment and the early distal tubule.
They do not affect the corticomedullary gradient since they lack action at the medullary thick ascending limb.
They decrease positive free water clearance but do not affect negative free water clearance.
[By inhibiting salt reabsorption, it is letting salt stay in the lumen, decreasing positive free water clearance. Think of it as coupling salt and water, like hitch xP
Negative free water clearance is ADH's job, it does not affect negative free water clearance]

This also explains why thiazides can be used in nephrogenic diabetes insipidus, when you can't reabsorb the free water because the kidney is unresponsive to ADH.
In the ascending loop, salts are reabsorbed and since the ascending loop is impermeable to water, free water is generated.  This salt free water is re-absorbed by ADH. All of this will be lost in the absence of ADH action.
Thiazides decrease positive free water clearance. So now, along with water, even salt is getting excreted. Long term, renin angiotensin aldosterone system gets activated, aldosterone will try to reabsorb more and more salt in the proximal convoluted tubule and water will get reabsorbed with it. More water is also reabsorbed in the distal convoluted tubule via ENaC subunits and aquaporin channels ^__^ (Here's a detailed explanation)

Another concept that you can learn from this post:
Thiazides can cause hyponatremia, loop diuretics do not. Why?
Diuretics can induce volume depletion and stimulate the release of antidiuretic hormone (ADH), which acts on the collecting duct to cause water reabsorption. However, this movement of water depends on a medullary concentration gradient.
Loop diuretics (eg, furosemide) impair this gradient, and therefore water reabsorption is diminished even with adequate ADH levels. That's why, loop diuretics are less frequently associated with hyponatremia.
Thiazide diuretics have no effect on the medullary gradient and water reabsorption is sustained.
Diuretics often cause a heightened thirst response leading to increased fluid intake and further elevations of plasma free water. Older women in particular have been found to be most susceptible to thiazide related hyponatremia.

That's all!


  1. Replies
    1. Thank you for the compliments Shraddha! =)

  2. Hey great explanation!!! After my lecture I was perplexed but now I see the light. I think you made a slight mistake in your calculation though. You wrote/solved for "Cosm" but I think it should have been CH20 in the problem below.
    Cosm = 0.6 - (0.6 x 700) / 230 = 0.6 - 1.5 = - 0.9
    [Negative sign tells you that water left salt behind in urine, body has retained 0.9 liters of water.

    1. Oh yes.. Updated it. Thank you for the correction! ^__^

  3. thank u....great job.

  4. This is really awesome. I understood nothing elsewhere until I came upon this. Thanks a ton! (Y)

    1. I am glad it helped you understand. You are most welcome! :)

  5. That was brilliant ! Wow!
    Thank you :)

    1. Thank you for the compliments, Nidhi (:

  6. Thanx for the gr8 explanation :)
    Can u plz answer my following question?!
    Why then loop diuretics induce hypernatremia ??!

    1. I don't know.

      Loop diuretics inhibit Na reabsorption. So you lose sodium and thus, loop diuretics cause hyponatremia.

      There is one site on the internet which does say loops can cause hypernatremia. Maybe because of the activation of renin angiotensin system, which makes you retain sodium in response to hypovolemia. Or maybe loops lose more water than salt. I am not sure how they could cause hypernatremia.

      But most books, including Katzung, state that loop diuretics cause hyponatremia.

  7. Thanku for the wonderful explanation. But i got a confusion.
    dont loop diuretics increase free water clearance rather than blocking it??

    1. You're most welcome! Oh I'll try helping you out (If I can).

      Why do you think loop diuretics increase free water clearance?

  8. Great. Helped a lot. Was reading about diuretics but nowhere was it explained what free water clearance actually was. Thanks a lot!

    1. I know. Same here! Had to do all kinds of stuff to get it.

      No problem!

  9. Thank-you. It helped a lot. Just one thing. 700*0.6/230 =1.8

  10. Hi, great explanation !

    Though it is a little bit confusing to me initially about the "positive" and "negative" free water clearance.

    I want to correct you on just one little thing:
    Use of thiazide in NDI is counterintuitive but just like u said, it decreases positive free water clearance (aka the urine now is concentrated with water). Distal delivery of sodium into collecting duct results in its reabsorption by using ENaC but the reabsorption can quickly got limited (because there is a limit to how many sodium ions can be reabsorbed using the channel each time). Since ADH is not working, the net effect is u will excrete a large amount of sodium-rich urine.

    Note that you get hypernatremia in ADH not because of sodium wasting, probably your sodium is on the low site but because of dehydration, the sodium got concentrated. And because you are dehydrated, RAAS is activated, therefore more sodium will be reabsorbed (as the activity of ENaC is increased by the action of aldosterone) and the body will try to restore the normal homeostasis.

    Back to the question, so how does thiazide help in NDI?
    Sodium and water wasting leads to more effort in proximal tubule to try to retain them. So less water will be excreted as urine distally. Note that, if u reabsorb back water, u do not have the risk of hypernatremia as water will dilute back the plasma.

    Of course, u have newer insight on why thiazide can be useful, which is like this

    On the question why loop diuretic causes hypernatremia as posted above, Im not sure.
    Loop diuretics more often cause hypokalemia and hypomagnesemia, rarely hyponatremia.

    It's because without reabsorption of NaCl in thick limb of loop of Henle, u loss the dilution ability of urine. Therefore, u end up having more diluted urine excreted out in the next few cycles. Perhaps this is the reason why it causes hypernatremia. It's because of (again) dehydration from excreting too much water.
    Though, to reach this stage, u must be diuretic overdose without drinking any water.

    Why doesn't hyponatremia happen often? because when u have increased distal delivery of sodium to distal tubule, the tubuloglomerular feedback in macula densa will be activated. GFR will be decreased, preserving the sodium, and therefore restoring the normal sodium homeostasis.

    Hope it makes sense.

    1. I got your explanation. Thank you so much.

      I didn't get what I should correct in my blog - Can you please pin point what exactly is mistyped?

    2. "This also explains why thiazides can be used in nephrogenic diabetes insipidus, when you can't reabsorb the free water because the kidney is unresponsive to ADH, that's when you try to decrease positive free water clearance by using thiazides."

      Rather than wrong, this is quite confusing. Because u only explain the first part of the mechanism, and not the second part.

      So how does decreasing positive free water clearance help in NDI? Because in the end, lots of urine is still produced and in distally sodium will be reabsorbed making the final product of excretion a quite dilute urine.

    3. Oh alright. I'll elaborate it further.

  11. Thanks for the explanation

  12. Waow
    I love the explanation. Can any one give me the significance of free water clearance

  13. Also is it possible to excrete urine more concentrated than plasma in the absence of ADH.


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