Function of renal medullary interstitial osmotic gradient

[E.S.Prakash]

I'm curious with what would occur if the hyperosmolarity of the renal
medullary interstitial osmotic gradient is lost. I haven't found a
real complete answer in the books. I've hit a dead end, this is what
I've come up with thus far:

Cause of loss of the Gradient:
1. Decreased ADH levels
2. ADH being ineffective [since ADH increases urea reabsorption and
urea recycling]
3. Failure of vasa recta to maintain the counter current exchanger
mechanism.

Effects:
A. Proximal tubule: Decreased H20 reabsorption (due to filtrate being
iso-osmolar to interstitium)

B. Thin descending limb of the Loop of Henle (LOH):
Decreased H20 reabsorption again.
Now tubular fluid is still not concentrated / iso-osmolar (?)

C. Thin ascending limb of LOH:
Decreased H20 reabsorption
Passive reabsorption of NaCl occurs
Urea enters the tubule (urea recyling)
Now tubular fluid hypertonic.

D. Thick ascending limb of the LOH:
Na, K, 2Cl reabsorbed through NKCC channels - - hypotonic tubular
fluid.

E. Cortical Collecting ducts: Na Cl actively reabsorbed -- hypotonic
tubular fluid

F. Medullary Collecting ducts: Na Cl actively reabsorped
Urea (?) -- dilute urine excreted.

Sorry if it seems incoherent, I am really confused at the moment.

Any help will be much appreciated.

Regards,

Waye Young
Year 2 Medical Student

[E.S.Prakash]

Waye Young:

The major mechanism that causes the development of an axial osmotic gradient in the outer medulla is the active transport of Na and Cl by the thick ascending limb of the loop of Henle. The transporter that mediates this is the NKCC2, present in the apical membrane of the cells of thick ascending limb. Inhibition of this transporter is the mechanism underlying the potent diuretic effects of furosemide (aka frusemide).

In the inner medulla, the accumulation of urea in the interstitium contributes substantially to the osmolality of the inner medullary interstitium. You are right - urea permeability of the medullary collecting duct is ADH dependent. Urea cycles from out of the inner medullary collecting duct into the medullary interstitium and accumulates there. The thin ascending limb of the loop of Henle is permeable to urea. Urea that passively enters the loop of Henle from the medullary interstitium remains in the tubular lumen until it gets to the inner medullary collecting duct. From studies of  urea transporter gene knockout studies, there is evidence that urea accumulation in the medullary interstitium contributes to the antidiuresis that can be achieved, especially under conditions of fluid deprivation. Also, in mice with urea transporters knocked out and placed on a high protein diet, the increased delivery of urea to the inner medullary collecting duct results in a urea mediated osmotic diuresis.

The fluid entering the descending limb of the loop of Henle is iso-osmotic (i.e. with respect to plasma). 25% of filtered Na and Cl is reabsorbed in the loop of Henle, whereas only 15% of the filtered water load is reabsorbed from the loop of Henle. This is why fluid entering the distal tubule is always hypotonic, no matter what the final osmolality of urine is. The final osmolality of urine is determined in the collecting duct and depends on the level of activation of water reabsorption by vasopressin.

To specifically answer your question, furosemide inhibition of the NKCC2 in the thick ascending limb abolishes the hyperosmolality normally developed there. Even if ADH were present and acted upon the collecting ducts, a polyuria would nevertheless result because the hypertonicity that drives water reabsorption from the collecting ducts would be lacking. The polyuria is considerable because 25% of the filtered NaCl is normally reabsorbed in the thick ascending limb and if this is inhibited - downstream segments of the nephron cannot compensate for it. Furthermore, the macula densa also reabsorbs Na and Cl via the NKCC2 - the transporter that furosemide inhibits. Thus, furosemide also shuts tubuloglomerular feedback down, and adaptive decrements in GFR in response to polyuria are inhibited. This is why loop diuretics are 'high ceiling' diuretics.

ADH is reported to have a chronic stimulatory effect on the NKCC2 and other transport mechanisms in the thick ascending limb as well [Ch 9 in Brenner and Rector's The Kidney, 2008] but I haven't come across anything specific as to how much ADH deficiency or ADH receptor mutations affects this process per se; presumably the acute antidiuretic effects of ADH with regard to water balance are largely accounted for by its actions in the collecting ducts both in humans and experimental animals.

You suggest failure of the vasa recta as a possible mechanism for loss of the gradient. That is correct. Normally, the very low blood flow in the inner medulla and countercurrent exchange of solutes between the ascending and descending limbs of the vasa recta allows the hypertonicity in the inner medulla to be maintained.

I can't however see how inhibiting the NKCC2 in the TAL would inhibit water and or solute absorption in the PCT. In a state that results in profound diuresis, typically reactive neurohumoral mechanisms operate to enhance solute and fluid recovery from the PCT and this may ameliorate the polyuria to some extent.  Profound diuresis reflexly activates the renin-angiotensin system and renal sympathetic outflow by inducing hypovolemia. For example, angiotensin II enhances Na, Cl and H20 reabsorption from the PCT. This mechanism was postulated to explain the paradoxical antidiuretic effect of thiazide diuretics given to individuals with diabetes insipidus, but other mechanisms possibly operate [see http://jasn.asnjournals.org/content/15/11/2948.full].

Prakash

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