Overview of Renal Structure and Function II Flashcards
Cpah=
UF * Upah/Ppah
Cpah is a good exogenous measure of:
RPF
What parameter measures the fraction of RPF that becomes filtrate?
How do you calculate it?
Filtration fraction
FF = GFR/RPF
Normal GFR =
Normal PRF =
So normal FF =
GFR = 120 mL/min RPF = 600 mL/min FF = 0.2 = 20%
FF is normally constant but can change when:
Volume status changes
When you think autoregulation, think:
Augmentation of reabsorption in PT/augmentation of delivery to distal nephron
Under what condition is autoregulation initiated?
Give an example.
Hypovolemia
Hemorrhage
What is activated when a pt is hypovolemic?
RAAS
Describe the pathway leading to the activation of RAAS.
Decreased CO –> Decreased arterial perfusion pressure –> Decreased Cl- sensed in macula densa –> RAAS
Why must RAAS be activated during a hypovolemic state?
To increase FF so GFR will be maintained
(FF = GFR/RPF; RPF is decreased so FF must be increased)
During autoregulation, the afferent arteriole is vaso___, while the efferent arteriole is vaso___.
Explain how this happens.
Vasodilated
Vasoconstricted
The efferent arteriole has many ATII receptors, while the afferent has few. Furthermore, ATII produces vasodilatory PGs that act on the afferent arteriole, as well as the myogenic response of the afferent arteriole vessel wall.
What 3 factors lead to vasodilation of the afferent arteriole during autoregulation?
- Few ATII receptors
- Vasodilatory PGs produced by ATII
- Myogenic responses of vessel wall
Autoregulation means more plasma becomes filtrate, and more filtrate is reabsorbed in the PT. What mechanism allows this to occur?
ATII causes vasoconstriction of the efferent arteriole, which becomes the peritubular capillaries. Hydrostatic pressure is reduced and oncotic pressure is increased in the peritubular capillaries, which favors reabsorption.
What causes the hydrostatic pressure of the peritubular capillaries to be lowered during autoregulation?
More plasma becomes filtrate
What causes the oncotic pressure in the peritubular capillaries to increase during autoregulation?
The same amount of protein is filtered at the glomerulus (if no glomerular damage present) but less volume reaches the peritubular capillaries
A pt on ibuprofen experiences a common side effect of GI bleeds. During a routine physical, her creatinine is noticed to be 90 mL/min.
What could explain this finding?
GI bleed –> hypovolemia –> autoregulation inhibited by NSAID because ATII can’t produce vasodilatory PGs –> less vasodilation of afferent arteriole –> decreased perfusion pressure + low GFR –> decreased creatinine clearance
What other classes of Rx besides NSAIDs may interfere with the efficiency of autoregulation?
ACE inhibitors (end in -pril)
Angiotensin receptor blockers (ARBs, end in -artan)
Direct renin inhibitor (aliskiren, pepstatin)
What happens to filtration fraction in volume expansion?
Decreases
(RPF increases, so FF must decrease to maintain normal GFR)
How does the kidney reduce FF during volume expansion?
Shut off renin/AngII
(just exactly the opposite of hypovolemia)
Where does bulk reabsorption occur? Fine tuning of solute and water reabsorption?
PT
Distal nephron
What is the most important element in controlling overall reabsorption, thus maintaining homeostasis?
Delivery to the distal nephron
What cells do the reabsorbing in a nephron?
Renal epithelial cells
How do renal epithelial cells increase their surface area for max absorptive capacity?
Microvilli and villi
What important component of renal epithelial cells would ONLY be found on the basolateral membrane?
Na+/K+-ATPase
(for Na+ reabsorption into peritubular capillaries; would be counterproductive on apical membrane)
Two functions of renal epithelial cell tight junctions
Cause polarity of cells
Separate unique apical transporters from basolateral membrane
Low or high capacity vs. resistance:
Proximal nephron?
Distal nephron?
Proximal = high capacity, low resistance
Distal = low capacity, high resistance
What effect does low capacity and high resistance of proximal nephron have?
Allows bulk reabsorption without creating steep gradients so the fluid exchange is isoosmotic
What effect does low capacity and high resistance of the distal nephron have?
Maintenance of steep gradient between urine and plasma for fine tuning
(T/F): Paracellular gradients are independent of the renal epithelial cell gradients.
False - paracellular transport follows transcellular pattern for each nephron segment
What influences paracellular transport?
Claudin proteins composing the tight junctions
Name 6 transport mechanisms in the nephron
Simple diffusion
Facilitated diffusion
Active transport
Coupled transport
Counter transport
Channels
3 things capable of simple diffusion?
Urea
CO2
Any lipid soluble thang
Which substance uses facilitated transport in nephron?
Glucose via glucose transports (GLUT)
What is the main O2-requiring process in the kidney?
Na/K-ATPase for sodium reabsorption
Name 3 ATPases found in the nephron
Na/K-ATPase
H-ATPase
Ca-ATPase
Coupled transport is always linked to the movement of which solute?
Na+
Name some substances that are cotransported wih Na
Glucose, amino acids, organic acids (lactic acid, ketoacid), phosphate, urate
Why is giving glucose with saline a good idea?
Glucose is coupled to Na+ transport; thus, it will help sodium transport
What is the purpose of coupled transport?
To avoid using energy in more than one step
(T/F): Sodium movement across renal epithelial cells into peritubular capillaries always requires energy.
True - can go through Na+ channels on apical membrane, which doesn’t require energy, but must use energy to cross Na/K-ATPase on basolateral membrane.
(Remember: Na/K-ATPase is biggest O2 consumer in nephron)
Name two antiporters in the nephron
Na/H
Cl/HCO3
What is the purpose of channels?
Name three found in the nephron.
Reabsorb when diffusion is not enough
Aquaporins, ion channels (Na, K, Cl), urea
Major difference between transports vs. channels
Channels are non-saturable
Transporters obey Michaelis-Menton, thus are saturable
What is the extent of the proximal nephron?
From PCT to end of TALH/beginning of macula densa
___% of total filtrate has been reabsorbed by the end of the proximal nephron
90%
(remember: proximal nephron built for bulk reabsorption)
Why is 90% of filtrate reabsorbed in the proximal nephron?
The distal nephron is geared toward fine tuning of filtrate; any excess solute delivered to the distal nephron will be lost in the urine
In which part of the kidney is the PCT? PST?
PCT = entirely in cortex
PST = down to corticomedullary junction
What makes up the peritubular capillaries?
CORTICAL efferent arterioles
(remember: juxtamedullary nephron efferent arterioles form the vasa recta)
If reabsorption in PT is isotonic, what is happening to the filtrate?
The composition changes, not the osmolarity
55% of __ and __ reabsorbed in PT
90% of ___ reabsorbed
100% of __ and ___ reabsorbed
55% NaCl and H2O
90% NaHCO3
100% glucose and amino acids
Glucose normally makes up ~___% of solute in thin ascending limb
0%
(normally 100% reabsorbed in proximal tubule
Name 12 things reabsorbed in PT
NaCl, H20, NaHCO3, glucose, amino acids, K+, urea, PO4, urate, lactate, pyruvate, ketoacids
If Na+ reabsorption in the PT was somehow inhibited, you would expect to also see reduced absorption of:
PO4, urate, pyruvate, lactate, ketoanions
(They are coupled to Na transporters)
What is secreted in the PT?
Organic anions and cations (drugs) and PAH
(think exogenous things; K+ not secreted until CD)
What is produced in the PT?
What is its function?
NH3 through glutamine metabolism
Binds H+ in lumen so acid can be excreted
What important feedback mechanism occurs in the PT?
Which solute can spill into urine if too high in blood and why: PO4 or Cl-?
PO4 - it has a transport maximum because it is reabsorbed via transporters
Cl- is reabsorbed through channels which are non-saturable
What would happen if we ate a meal large in protein and did not have glomerulotubular balance?
Increased load of protein filtered –> increased load delivered to distal nephron –> increased solute lost in urine –> hypovolemia –> shock
How is glomerulotubular balance able to prevent excess solute loss when we take in excess solute?
The same FRACTION of solute in reabsorbed but the ABSOLUTE amount increases
(i.e. if we usually take in 90g of protein but now take in 100g, 55% is still reabsorbed in PT but that’s now 55g instead of 49.5g)
What is the name for the process of reabsorbing more absolute amount of solute when more is delivered to PT?
Load-dependent reabsorption
Normal GFR
120 mL/min
Why does Na+ move into tubular cells through Na+ channels?
Na/K-ATPase keeps IC negatively charged; this promotes Na+ entry into tubular cells at the apical membrane
What would you expect to see in the urine of a pt with BG of 165 mg/dL?
NO GLUCOSE!
(Tm for Na-Glc cotransporter is BG>180-200 mg/dL)
Would you expect the urine of a pt with BS >180-200 mg/dL to be hypo-osmotic or hyperosmotic?
Hypo-osmotic
(glucosuria causes osmotic diuresis because Na-Glc cotransporter reaches Tm = less Na thus water reabsorption)
Normal plasma bicarb level?
24 mEq/L
(Remember: H = 24*pCO2/HCO3)
Describe how bicarb gets into tubular cells in the proximal nephron.
H+ is exchanged for Na in the tubular cell
In the lumen, H+ binds HCO3 to form H2CO3
CA on microvilli of tubular cells converts H2CO3 to CO2 + H2O
CO2 and H2O enter tubular cell via AQ1
IC CA converts back to H+ + HCO3
H+ is again exchanged for Na+…..
How does bicarb get reabsorbed once it’s in the tubular cell?
Na/HCO3 cotransporter on basolateral membrane
(3 HCO3 out for 1 Na in)
Beyond the reabsorption of bicarb, what purpose does the Na/HCO3 cotransporter serve?
Drives paracellular reabsorption of cations like Mg, Ca, Na
(cotransporter is electrogenic, so interstitial side is more negative than apical side, which drives cationic reabsorption)
What is the name of the CA inhibitor? What disease in particular does it treat and how?
Acetazolamide
Glaucoma
It prevents CA from forming HCO3 in tubular cells = no NaHCO3 reabsorption = water follows = diuresis = relieves pressure of glaucoma
Two things reabsorbed in thin descending limb
H2O and urea
(urea follows water!!!)
Why isn’t sodium reabsorbed in thin descending limb?
No Na+ channels
What is the tubular Na+ concentration in the hairpin turn of LOH? Urea concentration?
High
Low
What % of energy usage in nephron occurs in thin descending limb?
0
(passive diffusion only)
What transporter is present in thin descending limb?
AQ1
Which is higher in the hairpin turn of LOH: tubular or interstitial Na concentration?
Tubular
What % of energy usage in nephron occurs in thin ascending limb?
0
(passive diffusion)
What is reabsorbed in thin ascending limb? How?
NaCl
Passively diffuses through Na+ channels into hypotonic interstitium
What happens to water in the thin ascending limb?
Is not reabsorbed because thin ascending limb has no water channels = H2O impermeable
What % of urea is reabsorbed in thin ascending limb?
0
(Remember: water impermeable and urea follows water)
All segments past ___ are water/urea impermeable
Hairpin turn of LOH
Most of the 02 consumption in the nephron occurs where?
TALH
4 things reabsorbed in TALH
Na, Cl, Ca, Mg
What % of NaCl reabsorption occurs in the TALH?
20-25%
(this is why loop diuretics are so potent)
What is NOT reabsorbed in TALH?
Water or urea
(Remember: no segments past hairpin turn of LOH reabsorbs H2O/urea)
___ gets recycled in the medulla in the TALH
NH4+
What transporters are on the apical membrane of TALH?
NaK2Cl
ROMK
Explain the dual role of ROMK in the TALH.
- Since most K+ has been reabsorbed from the tubular fluid by the TALH, yet it is required to move Na and Cl into the cell via the NaK2Cl cotransporter, ROMK pumps the high IC [K+] back into the lumen
- K+ moving back into the lumen creates a + charged lumen = promotes _paracellular cation reabsorption _of Na, Ca, Mg
MOA: Loop diuretics?
Name three.
Block NaK2Cl cotransporter in TALH = less NaCl reabsorption = diuresis
Furosemide, bumetanide, torsemide
AE of loop diuretics is (hypo or hyper?) -calcemia and -magnesemia
Why?
Hypocalcemia and hypomagnesemia
Block NaK2Cl cotransporter = less K into cells = less pumped out via ROMK = less + charged lumen = decreased gradient for paracellular reabsorption of Ca/Mg
Bartter’s syndrome cause
Mutation in any transporter in TALH
(like having “congenital Lasix”)
Total % of NaCl reabsorption in LOH?
35%
What direct action does the afferent arteriole take when CO decreases?
Acts as a myogenic sensor and releases renin
What is the difference in glomerulotubular feedback and tubuloglomerular feedback?
**Think about what is doing the “sensing”**
- Glomerulo*tubular feedback = adjusting the absolute amount of load that’s filtered to keep the filtration fraction constant (done at the GLOMERULAR level)
- Tubulo*glomerular feedback = Cl- sensing by macula densa to adjust GFR (done at the TUBULAR level)
Distal nephron consists of:
DCT. connecting segment, cortical and medullary collecting ducts
DCT located in:
Entirely in cortex
How much NaCl reabsorption occurs in the DCT? Water?
5-8%
0% (past hairpin turn = water/urea impermeable)
What is the main goal of the DCT?
Maximally diluting urine by reabsorbing salt without water
What happens to the nephron’s ability to concentrate urine when the DCT is damaged?
Nothing
(Urine concentration occurs in the medullary TALH, which would still be in tact)
DCT is the major site of ___ reabsorption
Ca2+
Two functions of PTH on kidney
- Promotes Ca2+ reabsorption via Ca dependent protein on apical membrane of DCT
- Decreases PO4 reabsorption by downregulating Na/PO4 cotransporter in PCT
4 transporters in DCT
NaK-ATPase (basolateral)
Electroneutral NaCl cotransporter (apical)
Ca dependent protein (apical)
NaCa countertransporter (basolateral)
What is NCCT?
NaCl cotransporter on apical membrane of DCT
What blocks NCCT?
Thiazides
Congenital mutation = Gittleman’s
PTH-secreting tumor would lead to hypo or hyper -phosphatemia and calcemia
Hypophosphatemia (increased excretion)
Hypercalcemia (increased reabsorption)
Thiazide diuretic would cause hypo or hyper -calcemia
Hypercalcemia
(Blocks NaCl cotransporter = more active CaNa countertransporter = more Ca reabsorbed)
CaNa countertransporter kicks ___ out of tubular cell and brings ___ in
(# and ion)
1 Ca out for 3 Na in
Loops diuretics block ___ in the ___
Thiazides blocks ___ in the ___
NaK2Cl; TALH
NaCl cotransporter; DCT
Bartter’s is mutation in ___ in the ___
Gittleman’s is mutation in ___ in the ___
Any transport; TALH
NaCl cotransporter; DCT (“congenital thiazide”?)
A certain AE of thiazides can be used in the tx of another disease. Name the AE and the disease it treats.
Hypercalcemia
Kidney stones (prevents hypercalcuira)
__% of NaCl reabsorption occurs in the CD
2-3%
What is the function of the CD?
Produce steep gradients for maximal water conservation
Three types of cells found in CD
Principal
Alpha intercalated
Beta intercalated
Location and function:
Principal cells
Cortical and inner medullary CD
Na+/H2O reabsorption and K+ secretion
Where does K+ secretion mainly occur?
Cortical CD
Location and function:
Alpha intercalated cells
Cortical and outer medullary CD
Secrete H+ via H-ATPase or H+/K+-ATPase
Location and function:
Beta intercalated cells
Cortical and outer medullary CD
Secrete bicarb via Cl-HCO3 apical exchanger when we eat alkali foods
Where are principal cells in relation to intercalated cells in the CD?
Side by side
What is the osmolarity of tubular fluid in the CD?
What does this have to do with sodium reabsorption?
50 mOsm
Despite not much Na+ being available for coupled transport, a hugh electrical gradient exists for Na+ to move into cell because of - charged IC, so Na+ enters cells despite dilute tubular fluid
What does Na+ use to get into tubular cells in CD?
What does this cause?
ENaC on apical membrane
Electrogenic, making lumen more -, so K+ get secreted into lumen
Where does aldosterone work?
How does it work?
Cortical CD
Increases expression of NaK-ATPase and Na+ & K+ channels in apical membrane = increase Na reabsorption and K secretion
Two conditions that must be present for K+ wasting to occur
- Aldosterone
- Increased Na delivery to CCD
What is the only condition under which renal K+ wasting occurs?
Pt on diuretic that acts before the CD (loop, thiazide, acetazolamide, osmotics)
Why doesn’t a low salt diet cause K+ wasting?
Aldosterone is present but increased Na delivery to CCD isn’t because reduced ECFV causes increased PT reabsorption (autoregulation)
Why doesn’t a high salt diet cause renal K+ wasting?
Increased Na delivery to CCD but no aldosterone because of volume expansion
What is the relationship between increased Na delivery to CCD and K+ wasting?
Increased Na delivery to CCD = increased flux through ENaC = more negative lumen = increased K+ secretion
Which diuretics do not lead to K+ wasting? Why?
Those acting on CCD (spironolactone, triamterene, amiloride)
They do not increase Na delivery to CCD
Where does ANP act?
What is its primary function?
Why does it not cause K+ wasting?
Medullary CD
Increase NaCl excretion, thus cause naturiesis
K+ secretion occurs in cortical CD, thus ANP has no effect on K+
How does water get reabsorbed in the impermeable CD?
Through ADH-sensitive AQ2 and constitutively expressed AQ3&4
Describe how ADH causes expression of AQ2
Binds to V2 receptor on basolateral membrane of CD
Activates AC –> cAMP –> PKA –> phosphorylation of AQ2 vesicles –> AQ2 insertion into membrane
Where does the majority of water reabsorption in the CD occur? Why?
CCD
Tubular fluid there is 50 mOsm while the interstitium is 300 mOsm = huge water gradient causes water to exit via AQ; also, if too much water reached the medulla, it would wash out the high solute concentration
How does the medullary CD produce concentrated urine?
Urea has not been reabsorbed as water was reabsorbed through CCD, so the urine [urea] is very high once it reaches the MCD
ADH causes insertion of urea channels into inner MCD to allow packing of urea in interstitium = draws even more water out of tubular fluid
Is urine acidic or alkaline compared to plasma? Where does this change in pH occur?
Acidic (4.5 vs 7.4)
CD
3 mechanisms preventing excess delivery to distal nephron
TGF, GTB, autoregulation
When does NE affect filtration? How? Why?
Shock
Systemic constriction = less flow to entire kidney
Shunt blood back to heart and brain
