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)
5.
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
7.
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
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
20.
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
