Flashcards in Wall-2 Deck (99):
Are renal clearance and excretion rate the same thing ?
Volume of plasma cleared of a particular substance by elimination into the urine per unit time (Units: mL/min)
Not the same as excretion rate (the quantity of a substance in the urine per unit time; units: mg/min)
Use the same formula for any substance cleared by the kidney: renal clearance is the excretion rate/plasma concentration.
What is creatine clearance equal to ?
Creatinine clearance (CrCl) is approximately equal to the glomerular filtration rate (GFR) because creatinine only enters urine through glomerular filtration; it is not reabsorbed or secreted or metabolized to any great degree. CrCl is easily measured clinically and can give an overall picture of kidney function ( i.e. GFR). There is ~ 10% creatinine secretion, therefore creatinine clearance slightly over estimates true GFR.
What is the clearance ratio ?
State what the ratio values mean
Compares the clearance of a particular substance to the GFR
Can be used to get an idea of how the kidney handles this substance.
**Ratio = 1.0 means that the solute is handled like creatinine or inulin and its elimination is equal to the GFR.
**Ratio 1 means that the solute is filtered and actively secreted from the peritubular capillaries to the tubular fluid. (Ex: Potassium or hydrogen ion)
**Ratio = 0 means that either the solute is too large to be filtered (i.e. protein; OR a smaller molecule that is protein-bound) or it is filtered and 100% reabsorbed (i.e. glucose and amino acids should not be excreted to avoid wasting fuel)
What is the filtration fraction FF
Represents what percentage of renal plasma became glomerular filtrate
FF = GFR/RPF
Normal GFR is approximately 120 mL/min (10-20% lower in females)
Normal RPF is approximately 600 mL/min
Normal FF = 120/600 = 0.2
About 20% of RPF becomes glomerular filtrate (usually constant)
Can FF change ?
FF can change with a perturbation of volume state.
**Volume depletion (i.e. hypovolemia due to bleeding)
↓ cardiac output, with slight ↓ real arterial perfusion pressure, leading to activation of the renin-angiotensin-aldosterone system
In order to keep GFR constant, the kidney will ↑ filtration fraction (autoregulation)
↑ CO, ↑ RPF, ↑ perfusion pressure
Autoregulation causes a ↓ FF (opposite effects as described above for hypovolemia)
In the case of volume depletion, How is the afferent arteriole vasodialated ?
Angiotensin II produces vasodilatory prostaglandins. Afferent arteriole has minimal number of AII receptors
Myogenic response of the vessel will also cause dilation for more blood flow (less resistance)
In a condidion of volume depletion, How is the efferent arteriole vasoconstricted ?
Caused by local angiotensin II, efferent arteriole has abundant AII receptors
Since more plasma became filtrate in the glomerulus, the hydrostatic pressure of the efferent vessel (which becomes the peritubular capillaries) is now much lower than normal.
Also, since no protein was filtered at the glomerulus, the same amount of protein reaches the efferent arteriole in a smaller volume. Therefore, the oncotic pressure of the peritubular capillaries is now higher than normal. These
Starling forces enhance peritubular capillary reabsorption.
How can the autoregulatory response be disturbed ?
Preventing local production of AT II (i.e. ACE-inhibitors or angiotensin receptor blockers or direct rennin inhibitors)
Preventing production of vasodilatory prostaglandins (i.e. NSAIDs)
*Notice that these are some of the most commonly used agents and thus can produce a significant clinical problem.
How will the Kidney react to volume expansion ?
↑ CO, ↑ RPF, ↑ perfusion pressure
Autoregulation causes a ↓ FF (opposite effects as described above for hypovolemia)
Kidney will shut off renin and AT II productionNet effect is to augment delivery to the distal nephron; therefore, it is easier to excrete solute and water.
This system of autoregulation will be covered again in small group sessions, and there are summary tables available in the syllabus.
Where does the bulk of reabsorption take place in the nephron ?
Where is the fine tuning of the reabsorption take place ?
The Distal Tubule
What cell is key to reabsorption ?
The renal epithelial cell or tubular cell. Its apical membrane is exposed to the urinary space and the basolateral membrane is exposed to the interstitial space
What is the main purpose of the renal epithelial cell ?
Must reabsorb tubular fluid (ultrafiltrate of plasma), then send it through the cell or between the cells and back to the circulation
Need different transporters in apical vs. basolateral membranes
Need very large surface area in sections that will reabsorb huge amounts (i.e. proximal tubule); ↑ SA via villi and microvilli
What are tight junctions ?
Think of them as “gates”
Separate luminal transporters from basolateral transporters
Causes polarization of renal epithelial cell and separation of unique apical transporters from the basolateral side
What is the role of Na/K ATPase in renal absorption?
the cell is reabsorbing a huge amount of Na+ which must then be removed from the cell and returned to circulation
NO Na+/K+-ATPase on the apical side because it would be counterproductive!
How are transport proteins and ion channels used in renal absorption?
Specific transport proteins, ion specific channels, and water specific channels on the luminal and basolateral sides
Allow huge amounts of reabsorption
Includes transporters that link Na+ transport with other solutes
What are the two basic mechanisms for reabsorption ?
All reabsorption occurs either transcellularly (as described above) or paracellularly (through tight junctions).
Describe the proximal portion of the Nephron ?
The proximal portions of the nephron particularly the proximal convoluted tubule) are considered high capacity and low resistance.
Bulk reabsorption without the creation of steep gradients
Reabsorb a quantitatively large amount, but the osmolality of the tubular fluid remains the same (constituents changed)
Describe the distal portion of the nephron
The distal tubule is considered low capacity and high resistance.
Not for bulk reabsorption, but for maintenance of steep gradients between urine and plasma
What portion of the tight junctions influences paracellular absorption ?
Tight junctions are composed of claudin proteins that influence properties of paracellular reabsorption.
What are the six mechanisms of reabsorption ?
1. Simple Diffusion (Lipid Soluble)
2. Facilitated or carrier mediated diffusion (Glucose)
3. Active Transport (Na-K ATPase)
4. Coupled Transport (Link Trans to Na)
5. Counter transport (Cl-HCO3 Exchanger)
6. Channels ( Ion Specific or Aquaporin)
What are the differences between carriers and channels ?
Major difference between carriers and channels is that channels are not saturable. As long as there is an electrochemical gradient for the specific ion or water, it WILL move across a channel. On the other hand, coupled transporters have Michaelis-Menten kinetics; they are saturable and have a transport capacity. Once the transport capacity is exceeded, no more solute can be absorbed.
What is the size of the proximal tubule ?
Includes all parts of nephron from the proximal convoluted tubule exiting the glomerulus to macula densa (end of the cortical thick ascending limb of loop of Henle)
This entire segment is built for bulk reabsorption. By the time the tubular fluid reaches the macula densa, ~ 90% of the total filtrate has been reabsorbed, leaving the remaining nephron with a small volume to create fine, steep gradients, necessary for precise homeostasis.
Why do you want the bulk of material absorbed before it gets to the distal tubule ?
Everything is geared toward getting solutes reabsorbed proximally so the distal nephron is not overloaded. Because the distal nephron is not built for bulk reabsorption, any excess delivered solute will be lost in the urine.
Where is the proximal tubule located ?
Entirely in the cortex
Is bulk reabsorption a hypertonic process ?
Bulk reabsorption occurs isotonically
We just made an ultrafiltrate of plasma (same osmolarity); isotonic fluid enters and exits the PT, but its composition is altered by selective reabsorption.
What gets reabsorbed in the proximal tubule ?
Approx. 50-55% of total filtered load of NaCl and H2O
Approx. 90% of NaHCO3
100% of organic nutrients (glc, AAs)
What are the first three of eight functions of the proximal tubule ?
1. Bulk Reabsorption
2. 50-55% of total filtered load of NaCl and H2O. Approx. 90% of NaHCO3
100% of organic nutrients (glc, AAs)
3. Also site of organic anion and cation secretory pathways, including PAH
Major route of drug excretion
What are the last 5 of eight functions of the proximal tubule ?
4. PO4 , urate, and organic anion reabsorption (lactate, pyruvate, ketoanions)- linked to sodium coupled transport protiens
5. NH3 production through glutamine metabolism—important in acid/base balance
6. Glomerulotubular balance (different from tubuloglomerular feedback at macula densa, discussed in previous lecture)
7. Urea reabsorption ( parallels water reabsorption)
What is the filtered load ?
GFR x Px
What is the transport maximum ?
Transport Maximum = Tm
Exists for transporters with Michaelis-Menten kinetics because they can become saturated
What is glomerulotubular balance ?
Matching how much of the solute gets reabsorbed at the proximal tubule to how much gets filtered
Is GFR constant ?
Although we say normal GFR=120 mL/min, realistically GFR changes spontaneously moment to moment, depending on whether we are standing, eating, running, walking, etc.
What happens if GFR is increased by 20% ?
If GFR increased 20% after a protein load, there would be a large increase in the absolute amount filtered. If excess filtrate reached the distal nephron , the distal nephron could not handle it and excess solutes would be lost, eventually resulting in shock from hypovolemia.
When GFR is increased how do you prevent hypovolemic shock ?
To prevent this loss, the proximal tubule will continue to reabsorb 50-55% of the filtered load even when GFR increases (load dependent reabsorption).
The absolute amount of filtrate reabsorbed by the proximal tubule increases, but the fraction of filtrate reabsorbed stays constant.
The proximal tubule functions in a load-dependent manner; filter more → reabsorb more.
**Reabsorption is kept in the section of the nephron that is designed for reabsorption
What does the Na/K ATPase pump actually do ?
Keeps intracellular [Na+] low (10-30 meq/L) and makes cell interior negatively charged; this creates a huge electrochemical gradient for Na+ to enter the cell at apical membrane
Coupled transport proteins do not work unless both components bind to the transporter (i.e. Na+ with glc, PO4, urate, amino acid,organic anion)
How does an antiporter work ?
Antiporter—Na+ into cell, H+ exits cell
Is the Na channel saturable ?
Is the Na - Glucose transporter saturable ?
Na+-glucose transporter—a saturable carrier
As blood glc increases, filtered load increases. The Na+-glucose transporter will reabsorb more and more up to the point of saturation. After that, further increases in blood glc will still increase the filtered load, but more glc is not reabsorbed and is instead lost in the urine (glycosuria).
What condition would you commonly see saturation in the Na-Glucose transporter ?
This is seen in uncontrolled diabetics. Transporters are saturated when blood glc >180-200 mg/dl.
The excess glc in tubular fluid then disturbs the function of the remaining tubular segments, acting as an osmotic diuretic (increased NaCl and water excretion)
What is the main transport protein in H2CO3 reabsorption ?
Na+/H+ antiporter—H+ ions are extruded into lumen where they bind the filtered load of HCO3
How does HCO3 move into the tubular cell ?
Carbonic anhydrase (located at microvilli along the brush border of tubular cells) converts carbonic acid into CO2 and H2O, which then move into the tubular cell through constitutively expressed aquaporin 1
What happens after carbonic anhydrase degrades the enzyme and it is reabsorbed ?
Intracellular CA then converts CO2 and H2O back to H+ (which cycles back into the tubular lumen) and HCO3-
What is the fate of the HCO3 after it has been reabsorbed ?
HCO3- leaves the cell on the basolateral side through a specific cotransporter with Na+ (3 HCO3 out, 1 Na+ in); this transporter is electrogenic, resulting in a more negative charge on the interstitial side of the tubular cell
What is the driving force for the paracellulat absorption of cations ?
What is Acetoazolamide ?
Acetazolamide is a carbonic anhydrase inhibitor (used in rx of glaucoma) that will inhibit NaHCO3 reabsorption leading to increased excretion of NaHCO3 and water
What is the osmolality of the fluid that enters the loop of henle?
Isotonic when it enters.
What part of the LOH does passive transport take place in ?
Via passive transport in the thin descending loop.
What molecule is responsible for H2O reabsorption ?
Aquaporin-1. Urea will be absorbed and follow the H20 as it is absorbed.
What is the correlation between water and urea absorption ?
Good rule of thumb: Urea follows water (anywhere H2O is absorbed, so is urea!)
Is the thin descending loop permeable to NaCl ?
What happens to NaCl as it travels down the LOH ?
Minimal NaCl permeability because there are no Na+ channels
[Na+] continues to increase as loop descends into hypertonic medulla
Highest tubular salt concentration is at the “hairpin turn”; tubular [NaCl] is higher than interstitial conc.; also, low tubular [urea]
Where is NaCl reabsorbed in the LOH ?
Thin ascending limb—still passive transport, but a change in transport properties
NaCl passive reabsorption—Na+ channels present, so high [NaCl] in tubular fluid can passively move to the interstitium
H2O impermeable (no water channels)
In the LOH where does active reabsorption of NaCl take place ?
Thick ascending limb (cortical and medullary segments)—active NaCl transport (energy requiring)
Approx. 20-25% of NaCl reabsorption
H2O and urea impermeable (remember, all segments distal to the hairpin loop are water and urea impermeable; we are reabsorbing salt, but virtually no H2O)
What segment of the LOH requires O2 ?
Because the basolateral Na+/K+-ATPase is working to create ion gradients, this segment requires O2. Critical for producing hypertonic medulla; if medulla isn't hypertonic, urine can't be hypertonic
Therefore, essential for maximal dilution and concentration of urine.
Other than NaCl reabsorption what else takes place in the Thick ascending limb ?
Also major sites of Ca++ and Mg++ reabsorption and NH4+ recycling in the medulla
How does the thick ascending lomb actively absorb Na ?
Na+/K+-ATPase creates concentration gradients
Unique luminal Na+/K+/2Cl- transporter moves these ions into the tubular cell
transporter requires Na+, K+, and 2Cl- to be bound in order to function
Since we have reabsorbed most of our K+ by this point (we are in the thick ascending LOH) not as much is available in the tubular fluid; what is done in order to supply K+ ions to the lumen
K+ channel (a.k.a. ROMK) is inserted in the luminal membrane.(intracellular K concentration is very high due to Na-K ATPase).
Thus, K+ is recycled along the thick ascending limb, Na+ is pumped out of the tubular cell by the Na+/K+-ATPase, and Cl- exits the tubular cell via basolateral Cl- channels
In the thick ascending limb what is done to promote the absorption of Na+, Ca+, and Mg+.
K+ entry also gives the lumen a positive charge, which promotes paracellular reabsorption of Na+, Ca++, and Mg++
What loop diretics will block the Na, K, Cl transporter ?
Furosemide—Lasix®, bumetanide, torsemide
How much Na is reabsorbed in the thick ascending LOH ?
Since 25% of Na+ reabsorption occurs at this site, loop diuretics (furosemide) are very powerful natriuretic agents!
Blocking this transporter results in a high solute load delivered to the distal nephron, which then obligates water excretion and a high urine flow rate
What effect will Loop Diuretics have on the Na, K, Cl transporter ?
Also, since no lumen positive charge is created without the function of the Na+/K+/2Cl- transporter AND K+ channel, furosemide will cause a decrease in Ca++ and Mg++ reabsorption (i.e. increased urinary excretion).
What effects will an inactivating mutation on the transporters of the thick ascending loop have ?
Any inactivationg mutation in any of these transporters (including the K+ or Cl- channels) will result in Bartter's syndrome, resembling “congenital Lasix”
What percent of the Na reabsorption does the LOH have, as a whole ?
35 % of total Na reabsorption
What is at the end of the thick ascending LOH ?
The Macula Densa
What is Tubuloglomerular feedback (TGF)
1.Remember, the end of the cortical thick ascending limb is the macula densa, which senses [Cl-].
2. Since an increase in solute delivery will increase [Cl-], the MD thus senses an increase in delivery to the distal nephron. 3.If too much delivery is sensed, the MD will signal the glomerulus to slow down (decrease filtration) by constricting the afferent vessel.
4. If there is a drop in renal perfusion pressure, the autoregulatory response described earlier (IV.D.a.) will largely maintain GFR.
What can the afferent arteriole do in response to a lowered flow ?
The afferent arteriole is also a myogenic sensor itself, so it can release renin in response to low flow or low arterial pressure to the afferent arteriole.
What is the purpose of TGF ?
The purpose of TGF and GTB (see VI.G.e.) is to protect the distal nephron from over-delivery. The distal nephron needs limited delivery to create steep gradients that are necessary for homeostasis. You will see this main goal of the nephron over and over again!
What is the portion of the nephron after the macula densa ?
Distal convoluted tubule (DCT)
*Note: the text refers to the DCT as simply the “distal tubule”; be sure to distinguish this region from the “distal nephron,” which includes DCT, connecting tubule, and cortical and medullary collecting duct
Where is the DCT ?
Entirely in the cortex
Is NaCl absorbed ? What about H2O and Urea ?
5-8% of NaCl reabsorption; H2O and urea impermeable (still reabsorbing salt without water)
The DCT is the main site of reabsorption for what molecule ?
Major site of calcium reabsorption and regulation
parathyroid hormone acts here to promote Ca++ conservation. PTH also increases urinary phosphate excretion by decreasing the expression of the Na/PO4 cotransporter in the proximal convoluted tubule
What are the transporters of the DCT ?
same Na+/K+-ATPase on basolateral side
Electroneutral Na+/Cl- cotransporter on apical side (a.k.a. NCCT)
Ca++ dependent protein on apical side that is responsive to PTH (conserves Ca++)
Ca++/Na+ countertransporter on basolateral side; 3 Na+ in for every 1 Ca++ out of tubular cell
What do thiazide diuretics do
inhibit Na+/Cl- cotransporter
Since less NaCl is reabsorbed at the DCT, thiazides are not as potent (only cause moderate salt/water excretion)
Thiazides also cause a decrease in urinary Ca++ excretion because the Ca++/Na+ countertransporter is more active when the Na+/Cl- cotransporter is blocked
What are thiazides used to treat ?
Thiazides are used to treat patients prone to developing kidney stones; by decreasing urinary Ca++ excretion, you can prevent hypercalciuria and limit formation of Ca++ stones (calcium oxalate stones)
Most commonly used antihypertensive agent
What will a selective inhibition in the Na/Cl cotransporter result in ?
What is the major function of reabsorption in the collecting duct ?
Reabsorption of 2-3% of NaCl filtered load
Critically important for creating steep gradients (no bulk reabsorption)
all fine tuning and determination of ultimate urinary composition happens here
What is the structure of the collecting duct ?
A cortical segment and Outer segment with inner and outer portions
What are the principle cells in the collecting duct ?
Principal cells (cortical CD and inner medullary CD) are important for salt/H2O reabsorption. K+ secretion occurs mainly in the cortical collecting duct in principal cells.
Cortical collecting duct is the only site in the nephron where aldosterone works to conserve salt and stimulate K+ secretion.
What do the inter calculating cells do in the collecting duct ?
Intercalated cells (cortical CD and outer medullary CD) are important for acid-base balance; alpha intercalated cells secrete H+ via H+-ATPase or H-K ATPase. H+ secretion by intercalated cells is stimulated by aldosterone.
Do inter calculating cells and principle cells have similar functions in the collecting duct ?
Intercalated and principal cells sit side-by-side in the collecting duct although they have different jobs.
β-intercalated cells are also present; if you eat a lot of alkali food (vegetarian), these cells will secrete HCO 3-.(Cl-HCO3 apical exchanger)
How is Na transported in the collecting duct ?
Since most NaCl has already been reabsorbed, the tubular fluid is more dilute (50 mosm). There is not much [Na+] for coupled transport, but a huge Na+ electrochemical gradient still exists because of the negative cell interior (created by ATPase). Therefore, Na+ moves through an apical Na+ channel (epithelial sodium channel—ENaC).
How is aldestesterone transported in the collecting duct ?
Aldosterone binds to its receptor to activate transcription of proteins to increase Na+ and K+ transport (Na+/K+-ATPase on basolateral side and Na+ and K+ channels in apical membrane)
How is Na reabsorbed in the collecting duct ?
Reabsorbing Na+ through ENaC is electrogenic, creating a negatively charged lumen. The negative charge then favors the secretion of K+ into the lumen. This is why Na+ reabsorption is linked to K+ secretion.
Is K secreted in the collecting duct ?
K+ secretion keeps total body K+ normal (usual diet has 50-100 meq/day, so kidney must excrete the same amount to maintain neutral balance).
In order for excessive K+ secretion (renal K wasting) to occur, you must have both aldosterone and Na+ delivery to the cortical collecting duct.
How do the kidneys react to a low salt diet ?
Low salt diet—kidney needs to conserve Na+, so aldosterone is released; however, the kidney also enhances proximal reabsorption (due to slight decrease in ECFV), such that less Na+ is delivered to the distal nephron. As a result, less negative charge is generated in the lumen from Na+ reabsorption at the distal nephron, and the drive for K+ secretion is decreased. Therefore, K+ is not wasted!
How do the kidneys react to a high salt diet ?
High salt diet—aldo is turned off because you are volume expanded. Therefore, less Na+ is reabsorbed ( less lumen negativity) and less K+ channels are inserted in the apical membrane such that NaCl is excreted without K+ wasting.
What will diuretics that act before the CT do to K+ in the collecting duct ?
Diuretics that act before the CD (loops, thiazides, osmotic diuretics, carbonic anhydrase inhibitors) will waste K+ because they cause more Na+ to reach the cortical collecting duct. They also lead to increased Aldosterone by leading to negative sodium balance. The combination of increased Na+ delivery and aldo stimulated Na+ reabsorption creates a more negatively charged lumen and therefore enhanced K+ secretion.
What do diuretics acting on the cortical collecting duct do to K secretion ?
Diuretics acting at the cortical collecting duct do not increase delivery of sodium and in fact lead to decreased K secretion (spironolactone, amiloride, triamterene). ANP acts largely in the medullary collecting duct to increase NaCl excretion and therefore does not alter K secretion (which occurs in the cortical collecting duct).
How is concentrated urine made in the CD ?
Water is reabsorbed
Is the CD permeable to water and urea ?
CD is naturally impermeable to H2O and urea; however, there are preformed H2O channels (vasopressin sensitive aquaporin, aquaporin 2) in the cytoplasm of cortical and medullary CD tubular cells
When is vasopressin released ?
Increased plasma osmolality (due to water restriction) signals the release of vasopressin (ADH), which binds its V2 receptor at the CD basolateral membrane.
What does Vasopressin do ?
Vasopressin binding then activates a G-protein coupled pathway to activate cAMP and eventually insert the preformed channel (aquaporin 2) into the luminal membrane.In addition, different aquaporins (3 and 4) are constitutively expressed at the basolateral membrane to return H2O to circulation.
With the aquaporin formation in the cortical collecting duct does the concentration gradient favor H2O absorption ?
Tubular fluid= 50mosm; renal cortex interstitium= 300mosm; with the H2O channels in the tubular cell, there is an enormous concentration gradient driving water reabsorption in the cortical collecting duct. The majority of water reabsorbed in the collecting duct ,when we make concentrated urine, is occurring in the cortical collecting duct, thus limiting delivery to the medullary collecting duct.(Normal plasma, interstitial, and intracellular osmolality is about 290-300 mosm/kg H2O)
If you drink excess H2O what will happen to Vasopressin concentration ?
If you drank excess water, the opposite situation would occur; plasma osmolality would decrease, shutting off vasopressin. Thus, the aquaporins would stay in the cytoplasm, and tubular fluid would remain at 50mosm to produce dilute urine
How much of medullary solute is urea ?
50% of medullary solute is urea; since you can’t make final urine any more concentrated than the inner medulla, you must pack urea into the inner medulla to allow maximum concentration.
Where does water reabsorption in the collecting duct happen ?
Most water reabsorption in the CD occurs in the cortical region (this is a good thing—if too much water reached the medulla, it would wash out the high solute concentration). As H2O is reabsorbed, urea is left behind (everything is urea impermeable!); so, as you enter the inner medullary CD, urine [urea] increases significantly…in fact, now urine [urea] is higher than inner medullary [urea]
What is vasopressin's role other than H2O reabsorption ?
vasopressin exerts its second function—ADH inserts urea channels in the tubular cells of the inner medullary collecting duct to pack more urea in the interstitium. By recycling this waste product, the kidneys conserve even more water (amazing!).
Can any processes alter the fine tuning of the CD reabsorption ?
This fine-tuning system can be messed up by anything that causes an increase in solute excretion (i.e. glycosuria, diuretics), because the concentration gradient between tubular fluid and interstitium is broken down. In these cases, even maximal ADH can’t maximally concentrate the urine, and Uosm will approach plasma osmolality. Solute excretion obligates water excretion.