The document discusses the countercurrent multiplier mechanism in the kidney which allows it to concentrate urine. It describes how active transport of NaCl out of the thick ascending limb creates an osmotic gradient down the loop of Henle. As fluid moves through the thin descending limb, it becomes more concentrated due to water exiting into the hyperosmotic interstitium. The vasa recta help maintain this gradient by recycling urea and NaCl between the medulla and loop of Henle. Antidiuretic hormone regulates water reabsorption in collecting ducts to concentrate or dilute urine as needed. While the basic mechanism is understood, some aspects like solute transport in the thin descending limb and inner medulla remain unclear.

1. Countercurrent Multiplier
(the original pyramid scheme)

2. Overview
• Concentration mechanism
– Role of the thick ascending limb
– Role of the thin descending limb
– Role of vasa recta
– Role of the collecting ducts
• Kidney’s response to diuresis/anti-diuresis
• Current thoughts/active research

3. Concentrating ability of the
Kidney
• Main role of loop of Henle
• Enables “zones” of concentration
– Proximal medulla/cortex ~300 mOsm
– Deep medulla ~1200 mOsm

4. Concentrating ability of the
Kidney
• Major contributors
– NaCl
– Urea
• Minor contributors
– K salts
– Non-urea nitrogens
– Hydrogen (through Na/H exchangers)

6. Let’s start backwards
• Thick ascending limb
– Impermeable to water (efflux of NaCl without
water following)
– Active transport of NaCl out of tubular fluid
• Through Na/K ATP-ase on basilar side
• Creates low intracellular Na gradient
• NKCC (Na/K/2Cl) co-transporter and Na/H
exchanger present on apical side
– ~40% of NaCl reabsorbed in TAL
– Availability of K is the rate limiting step

8. TAL
• Active reabsorption of NaCl is the
main step in countercurrent
multiplication
• NaCl is the main substance that
creates osmotic gradient in superficial
nephrons

9. TAL
• Deeper medulla contains longer loops
likely driven by urea (discussed later)
– May also have some sodium (under
investigation)

10. Thin descending limb
• Full of aquaporins and urea transport
channels
• Relatively impermeable to ion
excretion
– Superficial nephrons mainly excrete
water
– Deeper nephrons may add some solute

11. Thin ascending limb
• No active transport
• NaCl passively diffuses out through
gradient
– Water reabsorption in thin descending
limb makes for a highly NaCl
concentrated tubular fluid
• Impermeable to water
• Adds a small amount to osmotic
gradient

12. Putting it all together
• Isotonic fluid enters loop
• NaCl actively pumped out of TAL
• Creates hyperosmolar interstitium (due to
NaCl accumulation) and hypotonic fluid in
TAL
• Relative proximity of thin descending limb
to TAL causes excretion of water into
hyperosmotic interstitium

13. Putting it all together
• Fluid flows down loop, process
continues until gradient is created
• Amount one can concentrate urine
likely linked to length of loops of
Henle
– Kangaroo rat excretes ~5500 mOsm
urine and loops so long they extrude into
renal papilla and collecting system

14. • http://www.colorado.edu/intphys/Clas
s/IPHY3430-
200/countercurrent_ct.swf

16. Vasa Recta
• Direct flow from efferent
arteriole
• Runs parallel to the loop of
Henle
• Isotonic upon entering
• As it goes down medulla
– Initially will have efflux of water
and influx of NaCl
– As it exits, will efflux NaCl and
influx of water
• Without this anatomic
configuration, solutes would
be washed out of medulla
• Provides nutrients to medulla

17. Urea
• Thin descending limb permeable to urea
• TAL and beyond impermeable
• Urea transport channels present in
medullary collecting duct
• As cortex and proximal medulla urea-poor,
primary water efflux is seen leading to
concentrated (higher urea) fluid

18. Urea
• Distal collecting duct, urea flows out
down concentration gradient
– Suspected this is why inner medulla can
reach ~1200 mOsm while only about
600 mOsm can be explained by NaCl

19. Urea recycling
• Can be transported from interstitium
into descending tubule
– Since rest of loop impermeable, will
eventually be carried back to IMCD
• Studies show more urea in distal
tubule than enters from the proximal
tubule
– Likely because vasa recta carries from
medulla to descending loop (through UT-A2
transporter), then to IMCD

21. Antidiuresis
• Body wants to make low volume, highly
concentrated urine
• Cortex is iso-osmotic (~300 mOsm)
• Gradient goes down to inner medulla
ranging 600-1200 mOsm (depending on
urea reabsorption and length of loops)

22. Antidiuresis
• In late distal tubule
– ADH leads to aquaporins and water
reabsorption
• In cortical and superficial medullary
collecting ducts
– ADH leads to aquaporins and water
reabsorption

23. Antidiuresis
• In inner medullary collecting ducts
– ADH leads to aquaporins and water
reabsorption and UT insertion and
increased urea reabsorption down
concentration gradient, increasing
insterstitial osmolarity

24. Diuresis
• Body wants to make high volume, low
concentration urine
• Tubular fluid entering collecting hypo-osmolar
~100 mOsm (due to active NaCl
pumping in TAL)
• With absence of ADH, little to no water or
urea reabsorption in collecting duct

25. Diuresis
• Leads to less water reabsorption also
in descending tubule (but no change
to NaCl pumping in TAL)
• All this increases urine volume

26. Situations affecting concentrating
ability (not related to ADH)
• Usually result in hypo/hypernatremia
• Decreased sodium absorption
– Bartter’s, ATN
• Decreased solute (urea and NaCl)
– Poor intake, liver disease, CKD
• Increased medullary blood flow
(solute wash out)
– Hypercalcemia, hyperthyroidism

27. Still unclear
• Everything
– Several of these things are theories based
on mathematical models and indirect
measures
• Thin descending limb
– Solute handling (unclear how urea and
NaCl transported out of tubule with relative
lack of aquaporins in inner medulla portion
– Question of as yet unknown transporter,
mathematical models to suggest urea-Na or
urea-Cl cotransporter

28. Still unclear
• Vasa Recta
– Urea transporters (UTA1/3 in collecting
duct is known)
– here genetics have found UTA2 and
UTB in thin descending limb and vasa
recta
• Knock out mice shows each knock out by
themselves increases diuresis, but knocked
out together counter-acts this diuresis

29. Still unclear
• Outer medulla
– Short loops are anatomically separated
from ascending limbs, therefore
nullifying idea of countercurrent
multiplication
• NaCl handling in the inner medulla
– As there is no TAL
– Limbs that do reach inner medulla are
thin and don’t transport NaCl