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52 Cards in this Set
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tubule osmolality along the corse of the nephron |
the proximal tubule reabsorbs filtered fluid isosmotically; the thin descending limb of the loop of henle is permeable to water and the fluid osmolality increases (by water reabsorption) in parallel with interstitial osmolality in the medulla; as the descending loop makes the hairpin turn and becomes the thin ascending loop it becomes impermeable to water but permeable to NaCl which is reabsorbed passively ([NaCl] is higher in the lumen) and the tubular fluid osmolality decreases; in the thick ascending limb which is also impermeable to water there is active NaCl reabsorption which renders the tubular fluid hypotonic; this is the segment where free water is generated; as tubular fluid enters the cortical and medullary collecting ducts if there is antidiuretic hormone present as in water restriction these segments will become permeable to water and tubular fluid osmolality will equilibrate with the osmolality of the surrounding tissue; in the cortex the osmolality is the same as plasma and that is the osmolality that the tubular fluid will reach; still in antidiuresis as the fluid enters the medullary collecting duct the luminal osmolality rises sharply as the tubular fluid equilibrates with the hyperosmotic medulla; in the condition of excess water intake ADH is not present and the collecting duct remain impermeable to water; the fluid entering these segments is hyposmotic and as salt is reabsorbed it becomes increasingly hyposmotic |
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generating hyperosmolar medulla and urine |
the renal medullar is hyperosmotic during water diuresis and antidiuresis; single effect and countercurrent multiplier; distinct pattern of water and salt permeabilities along the loop of Henle; the ascending loop of Henle plays a key role in both the dilution and concentration of urine; the main function of the loop is to remove NaCl from the lumen and deposit it in the interstitium of the renal medulla; by separating tubule NaCl from tubule water it participates directly in the formation of dilute urine; because it deposits the NaCl in the medulla it contributes to its hyperosmolality and therefore indirectly to the generation of concentrated urine; the hyperosmolar medulla is the result of the dingle effect and counter current multiplier and the distinct water and salt permeabilities along the loop of Henle |
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how does the coutercurrent multiplication in the loop of henle work? stage 1 |
the stating condition is with isosmotic fluid (300 mOsm) throughout the ascending and descending limbs and in the interstitium |
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stage 2 |
the 'single effect' (the one thing that really causes the whole thing to be set up); Na Cl transport from the lumen of the ascending limb to the interstitium increasing osmolality (it is impermeable to water even in the presence of AVP) |
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stage 3 |
increasing osmolality rapidly equilibrates with the lumen of the descending limb (it is permeable to water) |
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stage 4 |
an 'axial shift' of tubule fluid along the loop of henle with a rapid equilibration between the lumen of the descending limb and the interstitium leading to osmolarities of 300, 700, 1000, and 1200 in the interstitium from top to bottom |
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the movement of NaCl in the TAL |
the TAL moves NaCl from lumen out to interstitium using a combination of transcellular and paracellular pathways |
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the movement of NaCl in the tAL |
the tAL transports NaCl passively driven by the concentration of NaCl in the lumen which exceeds that of the interstitium of the inner medulla |
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what about the tDL? |
the work of concentrating the NaCl in the lumen is performed here; the tDL has a high water permeability owed to a high expression of aquaporin 1 (AQP1); the tDL has a very low permeability to NaCl and a finite urea permeability resulting from the presence of the UT-A2 urea transporter; the interstitium of the inner medulla has very high [NaCl] and [urea] which provide the osmotic energy for passive water reabsorption which secondarily concentrates NaCl in the lumen of the tDL |
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concentrations of NaCl and urea in the kidney (cortex and medulla) |
in the interstitium [NaCl] and [urea] all rise along the axis from the cortex to the papillary tip of the renal medulla; in the outer medulla a steep rise in interstitial [NaCl] occurs owing to the pumping of NaCl out of the TAL that is largely responsible for producing the hypertonicity; the [urea] rises steeply from the middle of the outer medulla to the papilla; at the tip of the papilla urea and NaCl each contribute approx 1/2 of the interstitial osmolality |
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the kidney filtering and reabsorption of urea |
it filters urea in the glomerulus and reabsorbs about 1/2 of it in the proximal tubule; in juxatamedullary nephrons tDL and tAL secrete urea into the tubule lumen; finally the IMCD reabsorbs urea (if you are in antidiuresis); the fractional excretion may be as low as 15% (minimal urine flow) or as high as 60% or more (maximal urine flow)(when there is little to no reabsorption in the IMCD) |
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the case of antidiuresis in which maximal AVP produces minimal urine flow |
as the tubule fluid enters the tDL the [urea] is higher than it is in the plasma because urea is reabsorbed somewhat slower than water (about 50% of the filtered load of urea remains in the lumen at this level); all nephron segments from TAL to the OMCCD, inclusive, have low permeabilities to urea; in the presence of AVP however all segments from the CT to the end of the nephron have high water permeabilities and continuously reabsorb fluid; as a result luminal [urea] gradually rises beginning at the CT and reaching a concentration as much as 8-10 fold higher than that in plasma by the time the tubule fluid reaches the end of the OMCD; AVP increases water and urea premeability in this segment; in the IMCD the high luminal [urea] and the high urea permeabilities of the apical membrane (through the urea transporter UT-A1) and basolateral membrane (through UT-A3) promote the outward facilitated diffusion of urea from the IMCD lumen into the medullary interstitium; as a result urea accumulates in the interstitium and contributes about 1/2 of the total osmolality in the deepest part of the inner medulla |
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because of the accumulation of urea in the inner medullary interstitium |
[urea] is higher in the interstitium than it is in the lumen of the tDL and tAL of juxtamedullary (i.e. long loop) nephrons; this concentration gradient drives urea into the tDL and tAL |
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summary of the processes we just described |
1. reabsorption of urea from IMCD into the interstitium 2. secretion of urea form interstitium into the tAL 3. delivery of urea up into the cortex and back down through the nephron segments from the TAL to the IMCD; this is known as urea recycling |
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the converse situation in which there is water diuresis |
circulating levels of AVP are low; the kidney reabsorbs less water along the collecting duct; with low AVP levels the IMCD has lower permeability to both urea and water; the interstitial urea concentration falls |
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coutercurrent exchange- what about the vasa recta? wouldn't they wash away what was created? |
no; the blood flow through the medulla is relatively low corresponding to no more than 15% of total renal blood flow; most significantly the vasa recta have a hairpin configuration with the descending and ascending vasa recta both entering and leaving through the same region thus creating an efficient countercurrent exchange mechanism in the blood vessels |
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how does the countercurrent exchange mechanism work in the vasa recta |
as isomotic blood enters the hyperosmotic milieu of the medulla NaCl and urea diffuse into the lumen of the descending vasa recta whereas water moves in the opposite direction; the result is that the osmolality of the blood increases as the blood approaches the tip of the hairpin loop; as the blood rounds the curve and heads up toward the cortex inside the ascending vasa recta that blood eventually develops a higher solute concentration that the surrounding interstitium; as a consequence NaCl and urea now diffuse from the lumen of the vasa recta into the interstitium whereas water moves into the ascending vasa recta; the net effect is that the countercurrent exchanger tends to trap solutes in and exclude water from the medulla thereby minimizing dissipation of the corticomedullary osmolality gradient |
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medullary collecting duct in antidiuresis |
in the absence of AVP it is relatively impermeable to water, urea, and NaCl along its entire length; AVP increases its water permeability along its entire length; AVP increases its urea permeability along just the terminal portion of the tubule (IMCD); the collecting duct traverses a medullary interstitium that has a stratified ever increasing osmolality from the cortex to the tip of the papilla so the osmotic gradient across the collecting duct epi favors the reabsorption of water from lumen to interstitium along the entire length of the tubule |
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as fluid in the collecting duct moves from the cortocomedullary junction to the papillary tip |
the [NaCl] gradient across the tubule wall always favors the osmotic reabsorption of water; for urea the situation is different because the proximal portions of the collecting duct are all relatively impermeable to urea water reabsorption predominates in the presence of AVP and gradually causes luminal [urea] to increase in these segments; even when the tubule crosses the cortocomedullary junction, courses toward the papilla, and is surrounded by interstitial fluid with an ever-increasing [urea] the transepithelial osmotic gradient favors water movement into the lumen |
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summary: tubule fluid is |
isosmotic in the proximal tubule, is dilute at the end of the loop of henle, and then either remains dilute or becomes concentrated by the end of the collecting duct |
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summary: the renal medulla is |
hyperosmotic to blood |
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summary: NaCl transport generates |
a gradient across the ascending limb which is multiplied generated a steep osmolar gradient between cortex and papilla |
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summary: urea is responsible for |
a significant portion of the the inner medullary interstitial osmolality |
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summary: vasa recta maintain |
the medullary osmolality |
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water balance in the kidney is governed by what 2 things |
antidiuretic hormone and thirst |
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2 key principles of water balance in the kidneys |
the body senses and regulates serum osmolality (not serum sodium concentration); serum osmolality is regulated by regulating water balance (not sodium balance) |
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osmoreceptors of the CNS are located where and sense what |
osmoreceptors of the CNS appear to be located in 2 areas that breech the blood-brain barrier= the organum vasculosum of the lamina terminalis (OVLT) and the subfornical organ (SFO); specific neurons in these regions are able to sense changes in plasma osmolality; the osmosensitive neurons project to large diameter neurons in the supraoptic and paraventricular nuclei of the anterior hypothalamus |
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supraoptic and paraventricular neuclei of the anterior hypothalamus synthesize what and do what with it |
synthesize AVP (aka ADH), package it into granules, and transport the granules along their axons to nerve terminals in the posterior lobe of the pituitary; when stimulated by the osmosensitive neurons these magnocellular neurons release the stored AVP into the posterior pituitary which is an area that also lacks a blood-brain barrier, and then AVP enters the general circulation |
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levels of circulating AVP depend on |
both the rate of AVP release from the posterior pituitary and the rate of AVP degradation |
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AVP degradation |
the liver and the kidney contribute to the breakdown and the rapid decline of AVP levels when secretion decreases; the half life of AVP in the circulation is 18 mins |
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the second efferent pathway of the osmoregulatory system- thirst |
the osmoreceptors that trigger AVP release and the osmoreceptors that trigger thirst are located in the same area; also like the osmoreceptors that trigger AVP release they respond to the cell shrinkage that is caused by hyperosmolar solutions; however these thirst osmoreceptor neurons are distinct from the adjacent AVP ormoreceptor neurons |
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the change needed for ADH release |
small change in plasma osmolality; a mere 1% rise in plasma osmolality stimulates AVP release by a detectable amount |
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hemodynamic stimulus for ADH release |
although an increase in plasma osmolality is the primary trigger fro AVP release several other timuli increase AVP release including a decrease in effective circulating volume or arterial pressure, nausea, pain, and pregnancy; fairly large reductions in effective circulating volume (5% to 10%) are required to stimulate AVP release in similar amounts as the osmotic stimulus; however once the rather high threshold for nonosmotic release of AVP is exceeded AVP release rises steeply with further effective circulating volume depletion |
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the interaction between osmotic and volume stimuli on AVP release |
the effective circulating volume modifies the slop of the relationship between plasma AVP levels and osmolality as well as the osmotic threshold for AVP release; during volume depletion a low plasma osmolality that would normally inhibit the release of AVP allows AVP secretion to continue; this leftward shift of the osmolality threshold for AVP release is accompanied by an increased slope reflecting an increased sensitivity of the osmoreceptors to changes in osmolality; in volume depletion the body is willing to tolerate some hypoosmolality of the body fluids as the price for maintaining an adequate blood volume |
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in contrast to colume contraction, chronic volume expansion |
reduces AVP secretion; there is a rightward shift of the threshold to higher osmolalities and a decline in the slope; in other words volume expansion decreases the sensitivity of the central osmoreceptors to changes in plasma osmolality |
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cellular mechanism of ADH effect |
AVP binds to V2 receptors in the basolateral membrane of the principal cells from the cortical collecting tubule to the end of the nephron; receptor binding activates a Gs heterotrimeric G protein stimulating adenylyl cyclase to generate cAMP; the latter activates protein kinase A which phosphorylates unknown proteins that play a role in the trafficking of intracellular vesicles containing AQP2 and the fusion of these vesicles with the apical membrane; in conditions of low AVP AGP2 water channels are mainly in the membrane of intracellular vesicles just beneath the apical membrane; under the influence of AVP the vesicles containing AQP2 move to the apical membrane of principal cells of the collecting tubules and ducts; by exocytosis these vesicles fuse with the apical membrane this increasing the density of AQP2; when AVP levels in the blood decline endocytosis retrieves the water channel containing aggregates from the apical membrane and shuttles them back ot the cytoplasmic vesicle pool |
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summary: ADH is released as a consequence of |
osmotic and non-osmotic stimuli |
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summary: ADH acting through cAMP casues |
aquaporin 2 insertion in the apical membrane of principal cells of the collecting tubules rendering them permeable to water |
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urine concentration (antidiuresis) is the generation of what and it happens in the presence of what |
generation of hypotonic tubular fluid; generation and maintenance of medullary hypertonicity; presence of ADH |
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in the situation of excess water there would be secretion of urea into the |
inner medullary collecting duct; the fractional excretion of urea can vary from 15% in a situation of antidiuresis to 60% or more in water diuresis |
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urine dilution (water diuresis) is the generation of what and in the presence of what |
generation of hypotonic tubular fluid; in the absence of ADH |
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osmolar clearance definition |
volume of plasma cleared of excreted osmoles/min; if the urine volume is less than expected (less than the volume that contains excreted osmoles at a concentration equal to plasma osmolality) then there is a negative free water clearance and we are reabsorbing water (concentration of solute in urine is higher than the concentration of solute in plasma; is the volume is larger than expected then there is a positive free water clearance and we are getting rid of water |
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key concepts: tubule fluid changes in osmolality |
isosmotic in the proximal tubule then dilute by the end of the loop of henle then either remains dilute or becomes concentrated by the end of the collecting duct |
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key concepts: the renal medulla is what to blood |
hyperosmotic to blood |
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key concepts: NaCl transport generates |
a gradient across the ascending limb which is multiplied generating a steep osmolar gradient between cortex and papilla |
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key concepts: urea is responsible for |
a significant portion of the inner medullary osmolality |
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key concepts: vasa recta maintain |
the medullary tonicity |
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key concepts: antidiuretic hormone is released as a consequence of |
osmotic and non-osmotic stimuli |
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key concepts: ADH acting through |
cAMP causes aquaporin 2 insertion in the apical membrane of principal cells of the collecting tubules rendering them permeable to water |
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key concepts: antidiuresis is the generation of what is the presence of what |
generation of hypotonic tubular fluid; generation and maintainence of medullary hypertonicity; presence of ADH |
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key concepts: water diuresis is the generation of what is the presence of what |
generation of hypotonic tubular fluid; absence of ADH |
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quantification of water excretion or reabsorption |
Cosm=(Uosm(V))/Posm where Cosm= osmolar clearance, Uosm= excreted osmols, V= volume of urine, and Posm= plasma osmols; CH2O=V-Cosm where CH2O= free water clearance, V= volume of urine, and Cosm= osmolar clearance |
