Lecture 6: Tubular Fxn 1 Flashcards
Define fractional reabsorption (FR)
The fraction of the filtered solute that has been reabsorbed
What is the equation for determining fractional reabsorption?
FR = 1 - FE
Where does virtually all regulation of potassium excretion occur?
Connecting tubule (CNT)
Collecting duct (CD)
List four routes for water output from the body, identifying the output that is most closely regulated
Insensible loss (skin, lungs)
Sweat
In feces
Urine **
List a typical normal plasma osmolality (Posm) and the typical range for urine osmolality (Uosm)
Posm = 290 mOsm/kg H2O
Uosm = 50 - 1200 mOsm/kg H2O
Estimate the fluid intake needed to excrete an osmotic load of 600 mOsm/day if Uosm is equal to the normal:
A) max Uosm
B) Posm
C) min Uosm
A) 0.5 L
B) 2.0 L
C) 12 L
What are the values for minimum Uosm and maximum Uosm?
Minimum
50 mOsm/kg H2O
Maximum
1200 mOsm/kg H2O
What is the value of Posm?
300 mOsm/kg H2O
How much does the proximal tubule reabsorb of Na + anions and water?
2/3
List four general steps involved in isoosmotic reabsorption form the PT into the peritubular capillaries and list the driving forces for each step
Step 1: Na/K ATPase pumps sodium out to interstitium
Driving force: ATP
Step 2: at lumen side, uptake of Na + anions occurs
Driving force: electrochemical Na gradient
Step 3: transcellular reabsorption of water through water channels
Driving force: osmotic gradient
Step 4: bulk flow of water and solute from interstitium to peritubular capillaries
Driving force: convection/ Starling forces
What about the peritubular capillaries makes it easy to accept so much flow of solutes and fluid?
They are fenestrated
For transcellular transport, describe the energy sources for
Primary active transport
Secondary active transport
In moving solutes against their electrochemical gradients
Primary active:
ATP
Secondary active:
One solute moves down its concentration gradient in order to power the movement of another solute up its gradient
What kind of transport occurs in uniporters?
Facilitated diffusion
Movement due to single solute’s electrochemical gradient
Differentiate between transcellular and paracellular transport
Transcellular = through cell
Paracellular = between cells (via tight junctions)
Describe the driving force and pathway for paracellular solute reabsorption
List important examples of solutes reabsorbed this way in the PT
Diffusion across “leaky” tight junctions into the lateral interstitial space
Driving force = electrochemical gradient, PASSIVE TRANSPORT
Examples:
Na, Cl, Ca, Mg, K, urea
Why is paracellular transport important?
Helps kidneys lower energy costs
How would an increase in filtration fraction affect peritubular capillary oncotic pressure (Pi(PTC)) and how would that change fluid reabsorption in proximal tubule?
Both would increase
Increasing GFR increases peritubular capillary oncotic pressure
Define glomerulotubular balance (GTB)
Near linear relationship between filtration (GFR) and reabsorption in proximal tubule as a means of stabilizing excretion to make sure we don’t lose a lot of fluid to urine
Briefly describe mechanisms for GTB that involve changes in starling forces to PT and luminal mechanism
Starling force changes:
Parallel changes in filtration fraction and peritubular capillary oncotic pressure
Luminal mechanism:
Luminal flow rate - shear strain on PT brush border recruits apical co-transporters
List the FR in the PT for water, sodium, chloride, bicarbonate, nutrients (glucose and amino acids), and bone minerals (calcium, phosphate)
Water, sodium chloride = 2/3
Bicarbonate = 80-90%
Glucose, amino acids = 100
Calcium = 50-60%
Phosphate = 80%
Describe the most important examples of “asymmetrical” solute transport in the PT
Explain why such asymmetrical solute transport is energetically more efficient for the kidney
S1 = early PT
Low Cl reabsorption (little permeability)
S2/S3 = late PT
High [Cl] and reabsorption
Energetically more favorable to have asymmetry because it establishes a concentration gradient to act as driving force for Cl transport to go down its gradient
Describe reabsorption of sodium in the PT
Transcellular = active 1/2
Basolateral Na/K ATPase
Driving force: gradient at apical side to power Na uptake into cell
Things that establish Na apical gradient: 1) symporters with glucose, amino acids, phosphate
2) NH3 pumps out H to bring in Na
Paracellular = passive 1/2
Na reabsorption secondary to Cl paracellular reabsorption (which generates lumen positive potential)
Describe asymmetry in reabsorption of bicarbonate in PT
Transcellular reabsorption because of preference for early PT reabsorption
Important players:
NH3: to recycle H and bring in Na
H ATPase: helps recycle H
Carbonic anhydride: makes bicarbonate
NBC1: pumps out Na and bicarbonate into blood
Describe reabsorption of chloride into PT
Most occurs in late PT
Transcellular:
Cl anion exchange: powered by organic anions that move down their gradients from inside cell to lumen
NHE3 brings Na in and sends H out so that it can combine with anion and bring them in for recycling as an acid
Paracellular:
Tight junctions permeable to Cl in later PT and establish electrochemical gradient
Describe reabsorption of glucose in PT
100% reabsorbed transcellularly
SGLT2 = early PT
SGLT1 = late PT
Glucose pushed into blood via GLUT2 basolateral uniporter
Describe reabsorption of amino acids in PT
Majority transcellular
Na-coupled symporters will bring in sodium and amino acid
What is the role of amino acid reabsorption in high protein diet?
High protein diet induces hyper filtration through tubuloglomerular feedback:
More AA’s in tubular fluid means more Na will be brought in with symptorter - leaves less sodium to reach macula densa
Macula densa responds with sending signals to increase GFR
Describe phosphate reabsorption in PT
Transcellular:
Na-coupled symporter = NPT
How is phosphate reabsorption regulated?
Hormones PTH and FGF will induce endocytosis of NPTs (Na-coupled symporters) so as to reduce reabsorption of phosphate
Identify and describe the mechanism for a class of anti-diabetic drugs that acts in the PT
“Gliflozins” inhibit SGLT-2 to block reabsorption of glucose in early PT
Effect is that downstream SGLT in late PT will increase reabsorption of filtered glucose
Define transport maximum (Tm) and identify an important solute that has a Tm in the PT
Tm = maximum tubules can reabsorb before the remainder gets excreted
Glucose has Tm = 375 mg/min in PT
Describe the relative water permeability of the PT, thick ascending limb, DCT, connecting tubule (CNT) and collecting duct (CD)
Name the channel responsible for water permeability of the PT
PT = always permeable
High constitutive water permeability via AQP-1 in apical AND basolateral membrane
Thick AL, DCT = low/no permeability
CNT/CD = regulated water permeability
TF/P ratios for chloride initially rise as fluid moves along the PT. THis is because:
Bicarbonate is the anion preferentially reabsorbed in S1
Near isoosmotic reabsorption leads ot rising TF/P for chloride
For organic cation secretion:
A) describe the basolateral and apical transporters involved
B) list important examples of endogenous molecules and drugs that are substrates
A) cross basolateral via organic cation transporter (OCT); cross into lumen via cation antiporter
B) endogenous = creatinine, dopamine, epinephrine, histamine
Drugs = cimetidine, cisplatin
For organic anion secretion:
A) describe the basolateral and apical transporters involved
B) list important examples of endogenous molecules and drugs that are substrates
A) cross basolateral end via organic anion transporter (OAT) and into lumen via ATP pump (MDR or MRP) or anion exchanger
B) endogenous = creatinine, bile salts, fatty acids, oxalate, irate
Drugs = PAH, penicillin, furosemide
Describe secretion characteristics of organic anions in PT
Secretion not affected by protein binding
Limited by transport maximum
Inhibited by probenecid (inhibits OATs)
Briefly describe urate transport in the PT
Secretion and reabsorption occur in PT
Majority of urate is net reabsorbed
Describe hypouricemia
It can be a result of mutations to which transporters?
Uric acid lost to urine and blood levels decrease
GLUT9 and URAT1
What disease is associated with high P(urate)?
Hyperuricemia/gout
Can’t be secreted to urine and so levels accumulate in the blood
Name drug that can decrease P(urate) and explain its mechanism
Thiazides = competes for secretion
Probenecid = inhibits reabsorption
For loop of Henle describe transporters or other pathways for reabsorption of
Na, K, Cl, Ca, and Mg
In the thick AL, identifying the driving force for each
Predict effect of inhibiting NKCC2 or ROMK on reabsorption of each
NKCC2 = symporter for Na, Cl, and K
ROMK = transporter for K into lumen
CLC-KB = basolateral chloride channel
Paracellular cation transport for Na, Ca, Mg, and K (driving force = lumen positive trans-epithelial potential)
Inhibition of NKCC2 or ROMK would decrease reabsorption of solutes
What happens where there is high calcium levels in the blood?
High calcium levels would be sensed by CaSR, which will inhibit trans-epithelial potential and paracellular transport
This allows calcium to build in the urine until the level in the blood can get readjusted or regulated
What is Bartter’s syndrome?
Genetic loss of function mutation that involves impaired salt reabsorption because NKCC2, ROMK, or CLC-KB transporters are affected
And all 3 transporters work together in sync
If you could sample tubular fluid at the end of the cortical thick AL and measure its osmolality, what would you find?
The fluid would have a lower osmolality than the plasma
Explain why the thick AL is a diluting segment, appreciating that tubular fluid at the macula densa has a lower osmolality than plasma - regardless of the final osmolality of the urine
Thick AL is where salt comes out, but there’s no permeability for water, so water stays in and dilutes the little salt remaining
Why is it important to study changes in the hydraulic and oncotic pressure differences in the renal circulation?
Differences in glomerular capillaries can be used to calculate NFP = important GFR determinant
Differences in peritubular capillaries can be used to calculate net reabsorption pressure = important determinant of reabsorption of water and solutes in PT
What form of the Starling equation is used to describe filtration in glomerular capillaries?
GFR =
Kf [ (P(GC) - P(BS)) - Pi(GC)]
Where GC = glomerular capillary
BS = Bowman’s space
Why is there no sigma or Pi(BS) term in the starling equation for GFR?
Glomerular capillary endothelial cells do NOT have a large pore system - this means significant filtration of plasma proteins does not occur
Normal filtration barrier there is therefore “perfectly reflective) (sigma = 1)
So the filtrate would not contain a significant concentration of plasma proteins, therefore oncotic pressure in Bowman’s space = 0 (no need for Pi(BS))
What form of starling equation is used to describe reabsorption in peritubular capillaries?
Jv = Kf
[ P(PTC) - P(ISF) ] -
Sigma* [ Pi(PTC) - Pi(ISF) ]
PTC = peritubular capillary ISF = interstitial fluid
What does a negative value of Jv for the peritubular capillary form of starling equation indicate?
Net reabsorption
What does the area between the hydraulic pressure curve and oncotic pressure curve in the GLOMERULAR capillaries represent?
In the peritubular capillaries?
Glomerular capillaries =
Net filtration pressure (NFP)
Peritubular capillaries =
NFP also, BUT since oncotic pressure is greater than hydraulic, the NFP turns negative and is therefore best described as a net reabsorption pressure
How can GFR be increased according to the Starling equation?
Increase:
Kf
P(GC) - hydraulic pressure
Decrease P (BS)
And/or Decrease Pi(GC) - oncotic pressure
What is the best way to produce an isolated increase in GFR without change in RPF?
Increase P(GC)
Hydraulic pressure of glomerular capillaries
What is the best way to increase P(GC)?
Dilate afferent arteriole (decrease resistance)
Constrict efferent arteriole (increase Resistance)
OR for isolate increase in GFR (to keep RPF constant RVR can’t change):
Decrease in resistances of afferent and efferent arterioles
What is glomerulotubular balance (GTB)?
Increase in fluid reabsorption from PT into the peritubular capillaries following an increase in GFR
AKA load dependence
How can GFR be decreased according to the Starling equation?
Indicate the best way to produce an isolated decrease in GFR (no change in RPF)
Decrease Kf
Decrease P(GC) ***
Increase P(BS)
And/or increase Pi(GC)
How can P(GC) be decreased?
Constrict afferent article (increase resistance)
Dilate efferent arteriole (decrease resistance)
To produce isolated decrease in GFR (and keep RPF constant, RVR can’t change)
Equal increases in resistances of afferent and efferent arterioles
What is the term used to describe decrease in fluid reabsorption from the PT into the peritubular capillaries following a decrease in GFR?
also called GTB
Glomerulotubular balance
What are the main transporters responsible for sodium reabsorption in the
Thick AL
DCT
CNT/CD
Thick AL:
Na-K-2Cl cotransporter (NKCC2)
DCT: NaCl cotransproter (NCC)
CNT/CD:
Epithelial Na channel (ENaC)
What is the equation for fractional excretion of solute?
FE =
U(x) * Vdot / P(x) * GFR
What is the equation for fraction reabsorbed of a solute?
FR = 1 - FE
