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PHGY 312 > Renal L9- > Flashcards

Renal L9- Flashcards

1
Q

What happens to H2O reabsorption/lumen concentrations in antidiuretic conditions?

A

*Antidiuresis → not a lot of fluid in the body → want to concentrate the urine

Filtrate ~ 300 mOsm → same in S3 of proximal tubule
Thin ascending limb → high H2O permeability → reabsorption as go down in inner medulla to match interstitium
Bottom of Henle’s loop ~ 1200 mOsm (very concentrated interstitium)
Thin ascending limb → no H2O permeability, but passive NaCl reabsorption
TAL → active NaCl reabsorption (NKCC2)
Distal convoluted tubule ~ 120 mOsm (hypoosmotic)
CCD → ADH → H2O reabsorption following increase in interstitial osmotic solution
Urine ~ 1200 mOsm

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2
Q

What happens to H2O reabsorption/lumen concentrations in diuretic conditions?

A

*Diuresis → Too much fluid in the body → want to dilute the urine

Filtrate ~ 300 mOsm → same in S3 of proximal tubule
Thin ascending limb → high H2O permeability → reabsorption as go down in inner medulla to match interstitium (more dilutes, less gradient)
Bottom of Henle’s loop ~ 500 mOsm
Thin ascending limb → no H2O permeability, but passive NaCl reabsorption
TAL → active NaCl reabsorption (NKCC2)
Distal convoluted tubule ~ 120 mOsm (hypoosmotic)
CCD → NO ADH → only NaCl reabsorption, no H2O even though papillae has 500 mOsm
Urine ~ 60 mOsm

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3
Q

Where are the 2 main sites of H2O reabsorption in antidiuresis?

A
  1. Thin descending limb
  2. Collecting ducts due to effect of Anti-diuretic hormones (required)
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4
Q

What parameter of solution can be used as a measure for osmolarity? How does it vary in the kidney (Cortex → Medulla)?

A

Freezing point → much lower in the medulla because higher osmolarity

*Early evidence of the countercurrent multiplier

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5
Q

Which 3 ions contribute to the interstitial hyperosmolarity in the outer/inner medulla?

A

urea (the most)
Na
Cl

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6
Q

Why is the lumenal osmolarity still 300 mOsm in S3?

A

Because before that, in the proximal tubule, all reabsorption is done isoosmotically (water follows Na reabsorption)

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7
Q

Which segments of the kidney have the greatest osmotic permeability ?

A
  • Proximal convoluted tubule
  • Proximal straight tubule
  • Thin descending limb

In the presence of ADH (or AVP):
- Cortical collecting duct
- Inner medullary collecting duct

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8
Q

What is the countercurrent mutliplier in the loop of Henle?
What is it important for?

A

The process of using energy to generate an osmotic gradient that enables you to reabsorb water from the tubular fluid and produce concentrated urine

2 parts:
1. Stepwise Shift of Fluid
2. Loop of henle can generate a small “Single Effect” → create a small 200 mV gradient with active transport

Single effect multiplied along the length of the loop → longitudinal concentration difference ~ 200 mOsm/L → repeating the process would result in a final longitudinal concentration difference of ~ 900 mOsm/L in vivo
- Uses the small gradient generated laterally by active transport of Na to generate a strong longitudinal gradient between the cortex and the papillae in the kindey

*the longer the loop of Henle the greater the osmotic conentration in the medulla and in the tubular fluid at the bend of the loop

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9
Q

What is the countercurrent exchange?

A

Blood vessels making up the vasa recta have no active transport, they serve as passive, countercurrent exchanger by trapping solutes in the medulla → prevent dissipation of the longitudinal concentration gradient → essential for maintaining cortico-medullary accumulation of solutes
- Helps preserve the gradient

Ex: If the concentrated generated can only be of 10 mOsm → in a straight line the top is at 30, the bottom at 40
→ in a loop, the fluid coming down equilibrate the the fluid coming up so it already at 90 when it gets down → become 100 mOsm and then goes up and equilibrate the new fluid coming down

In both cases comes in at 30 mOsm and exits at 40 mOsm, but it the loop, reaches 100 mOsm at the bottom
*Heater analogy (ascending limb “pre-heats” the fluid of the descending limb)

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10
Q

What is the vasa recta?
How does it contribute to the countercurrent exchanger?

A

Vasa Recta = capillary network that supplies blood to the medulla of the kidney → follows the loop of Henle

*Vasa recta is permeable to water and solutes

Changes in the medullary blood flow affects the efficiency of the counter-current exchange mechanism → increased blood flow → proportionally more solute is washed out of the papilla → maximal urinary concentration is diminished

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11
Q

By which mechanisms, do Anti-diuretic Hormones stimulate water permeability?

A
  1. TM receptor (V2) activates cyclase through G protein → stimulates formation of cAMP from ATP → Protein kinase A:
    → phosphorylates aquaporin to active them further
    → Stimulates aquaporin synthesis and insertion in the membrane (more long term)
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12
Q

What is the effect of protein content in the diet on urinary concentration?

A

High protein diet → promotes urea accumulation in the inner medullary interstitium → increased concentration ability
No protein → loose ability to concentrate urine

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13
Q

What factors (6) modulate urinary concentration and dilution?

A
  1. osmotic gradient of the medullary interstitium from cortico-medullary junction → papilla:
    → Length of the loops of Henle
    → Rate of active NaCl reabsorption in the TAL (more NaCl delivery bc higher GFR or filtrate fraction enhances NaCl reabsorption and vice versa)
  2. Protein content of diet
  3. Medullary blood flow
  4. Osmotic permeability of the collecting tubule and ducts to water (AVP required for water permeability)
  5. Luminal fluid in the loop of Henle and the collecting duct (high flow diminishes efficiency of countercurrent multiplier → reduces osmolality of interstitium + less time for quilibration in the MCD)
  6. Pathophysiology (Central or nephrogenic diabetes insipidus → reduces plasma AVP levels or renal responsiveness to AVP)
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14
Q

What is the effect of central or nephrogenic diabetes insipidus?

A

In reduces plasma AVP levels or renal responsiveness to AVP → reduces concentration of urine bc can’t equilibrate in the medullary collecting duct

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15
Q

How does clearance of PAH differ at different plasma[PAH]?

A

*PAH is filtered and secreted
- At low concentration → very high clearance (~625 mL/min)
- Over 200 mg/dL, start decreasing as secretion gradually saturates
- At very very high concentrations, gets closer to inulin clearance as secretion is saturated and only depends on filtration

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16
Q

How does Glucose clearance differ at different plasma[Glucose]?

A

*Glucose is filtered and reabsorbed
- Below 200 mg/dL, no clearance, all reasorbed
- From 200 mg/dL and higher, clearance gradually increases as reabsorption transporters gradually saturate
- At very very high concentrations, clearance approaches inulin clearance as only the filtration rate influences (straight line)

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17
Q

How does inulin and creatinine clearance differ at different plasma concentrations?

A

Inulin = straight line ~ 125 mL/min → filtration rate

Creatinine:
- At very low plasma concentration, a bit is secreted so a bit higher clearance
- From 150 mg/dL and higher plasma concentration, straight line = inulin, only filtration (not reabsorption, nor secretion)

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18
Q

How do cells survive osmotic fluctations in the medulla?

A

They accumulate and release organic osmolytes → allow to keep water in when hyperosmotic medullary solutions and release water when hypososmotic solutions
- Inositol → mostly accumulates in outer medulla cells
- Betaine → linear increase from outer medulla to inner medulla (lower osmolarities)
- Sorbitol → accumulates only in the inner medulla (at very high osmolarities)
*Don’t accumulate in the cortex

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19
Q

What is GPC?

A

Glycerophosphocholine → accumulates in cells exposed to hypotonic solutions
- Accumulates in cells when high NaCl, Urea in lumen (others only depend on NaCl?)

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20
Q

What transporter/mechanism is responsible for accumulation and release of Sorbitol in the cells? (Osmolyte)

A
  • Transported in the cell by glucose transporters
  • Synthesized from glucose by the enzyme aldose reductase
  • In high osmolality → increased transcription of aldose reductase and osmolyte transporter genes → more intake of glucose → more sorbitol
  • Exported by specific transporter on the basolateral membrane
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21
Q

What transporter/mechanism is responsible for accumulation and release of Inositol, Betaine, Taurine in the cells? (Osmolyte)

A

Inositol:
- Co-transport —> 1 Na : 1 Inositol
- Transporter similar to SGLT2
- Elevated by Na gradient increase

Betaine and Taurine:
- Elevated by uptake via separated Na/Cl/Osmolyte cotransporters (1:1:1)

22
Q

What transporter/mechanism is responsible for accumulation and release of GPC in the cells? (Osmolyte)

A
  1. Enters the cell as Choline → PC → (PLase enzyme) → GPC
  2. GPC is constantly degraded by GPC-PDE → Choline + Glycerol-PO4
    High [NaCl] or [urea] increase GPC levels b yinhibiting its degradation → counteracting
23
Q

What does it mean for the intracellular osmolyes to be compatible? To be counteracting? Which ones are?

A

Compatible = They can increase inside the cell without disrupting the cell’s metabolism
Compatible: Sorbitol, Inositol, Betaine, GPC

Counteracting = Its accumulation protects the cell against harmful effect of urea (which is denaturing in addition to being a metabolite)
Counteracting: GPC

24
Q

What happens to osmolytes when osmotic pressure in the medulla falls?

A

Osmolytes are rapidly released from the cells, probably through swelling-activated anion channels

25
Q

What are the Osmotic diuretics?

A

*They act on the proximal tubule (2/3 water normally reabsorbed) → reduce reabsorption of water → overload of more distal segments

Act by holding water in the lumen of the proximal tubule: Put something that can’t be reabsorbed in the lumen → osmotic forces act to keep more water in the lumen even if absorption of NaCl and organic solutes

  • Mannitol
  • Glucose (in diabetes mellitus where transporters are saturated)
  • Acetazolamide —> carbonic anhydrase inhibitor, reduced bicarbonate reabsorption in the form of CO2
26
Q

What are loop diuretics? How/Where do they act?

A

Act in the Thick Ascending Limb (loop of Henle)
- Bumetanide and furosemide → NKCC2 inhibitors

27
Q

What are thiazide diuretics? Where/How do they act?

A

Act on the early distal tubule
- Hydrochlorothiazide → NCC inhibitor (inhibits salt reabsorption, which in turn inhibits H2O reabsorption)

28
Q

What are Potassium sparing diuretics? Where/How do they act?

A

Act on the Late distal tubule and CCD
- Amiloride and triamterene → ENaC blockers
*No wasting of K+ compared to other diuretics because it inhibits secretion of K+ as well

29
Q

What are the different types of diuretics?

A
  1. Osmotic diuretics (PT)
  2. Loop diuretics (TAL)
  3. Thiazide diuretics (Early distal tubule)
  4. Potassium sparing diuretics (Late distal tubule, CCD)
30
Q

What cell functions require potassium?

A
  1. Volume regulation → important determinant of osmolality and tonicity of intracellular fluid → gains/loss of K+ associated with swelling or shrinkage bc tonicity is kept constant
  2. Chemical reactions → high [K+] necessary for optimal action of many intracellular enzymes
  3. Cell growth and division → RNA funciton and protein synthesis requires K+
  4. Acid-base status
  5. Glucose uptake and glycogen synthesis → both increase when K+ uptale by cells is promoted by insulin
  6. Excitability and contractility → Difference un K+ activity between cellular and extracellular fluids determines resting Vm
31
Q

Why is K+ require for acid-base status of the cells?

A

Shifts in H+ ion are related to shift of K+ → reciprocity between cell [K+] and [H+]:
- Loss of K+ from cells → cell water becoming more acidic
- Gain of K+ by cells → more alkaline

32
Q

What is the physiological concentration of potassium in plasma and interstitial fluid?

A

3.5-5 mEq/L
Min ~ 3.0 mM and Max ~ 6.0 mM

33
Q

What are consequences of severe hypokalemia and severe hyperkalemia?

A

Severe hypokalemia → mental confusion, weakness, paralysis
Severe hyperkalemia → paralysis and lethal cardiac arrhytmias
*Transfer of only a small fraction (1-2%) of intracellular K+ into the ECV can lead to a deleterious increase in plasma [K+]

34
Q

Wht is the dirstribution of K+ between extra- and intracellular fluid compartments controlled by?

A
  1. The activity of the ATP-driven Na+/K+ pump
  2. Passive K+ permeability of cell membranes
  3. Acid-base status of the body fluids
  4. Hormones
  5. Exercise
  6. High tonicity of body fluids
  7. Cell breakdown (trauma, tumor lysis, myelitis)
  8. High plasma K+ itself → promotes K+ uptake by cells
35
Q

What factors influence plasma K+ levels?

A
  • Insulin
  • Epinephrine
  • Aldosterone
  • Acid-base status (reciproqual relationship)
  • ECF osmolar status
  • Exercise → release of small amounts of K+ can elevate K+ leaks
  • Cell lysis → Because of the very high intracellular [K+], doesn’t much cells lysed to increase extracellular levels
  • K+ gain/loss from the body
36
Q

How does insulin affect plasma K+ levels?

A

High levels of insulin after a meal stimulate muscle and liver cells to accumulate K+ at greater rate → limits the rise in plasma [K+] that would otherwise occur after a K+-rich meal
Increses in plasma [K+] are a stimulus to insulin secretion by the pancreas

37
Q

How does aldosterone affect plasma K+ levels?

A

Like insulin, aldosterone secretion is stimulated by high plasma K+
Aldosterone promots K+ uptake by muscle cells, but action is not as important as insulin’s
Uptake of K+ by muscle cells du to aldosterone &laquo_space;effect of aldosterone on K+ transport by renal (and other) epithelial cells

38
Q

How does high tonicity of body fluids influence K+ distribution between extra- and intracellular compartments?

A

Cell lose K+ in response to prolonged hypertonicity

39
Q

How does epinephrine affect plasma K+ levels?

A

Beta-adregenic agonists promote K+ uptake by muscle cells

40
Q

What are the general filtration/reabsorption/secretion movements of K+ along the kidney?

A
  1. Free filtration
  2. ~80% of filtered K+ is reabsorbed along the PT (irrespective of final urinary excretion)
  3. Another 10% of filtered load reabsorbed alon the TAL

→ K+ reabsorption continues along the distal tubule and collecting duct in low K+ states (20-40%)

→ Secretion of K+ occurs in the late distal tubule and in the cortical collecting duct (20%-180%):
Powerful sensitive K+ secretory mechanisms, always a bit active but can be stimulated by K+-rich diet → determines the rate of urinary K+ excretion and responds to the stimuli that regulate K+ balance

41
Q

What are the % of filtered K+ in the final urinary excretion across the range? (low, medium, high)

A

Low urinary K+ excretion → 1-3%
Normal urinary K+ excretion → 10%
High urinary excretion → 150% of filtered load

42
Q

How much K+ is present in plasma?
How much in filtered/day?

A

GFR = 150L/day
Plasma [K+] = 4.5 mEq/L

GFR*Plasma [K+] = 675 mEq/day filtered of K+

43
Q

What are the cellular mechanisms for K+ transport in the proximal tubule? (apical membrane)

A

K+ ions reabsorbed paracellularly (most important) and transcellularly

Lumen has a positive voltage in the late proximal tubule → drives reabsroption of K+ through tight junctions of the leaky epithelium

44
Q

What are the cellular mechanisms for K+ transport in the thick ascending limb? (apical membrane)

A
  • NKCC2 (Na, K, 2xCl) co transporter (driven by inward chemical gradient for Na+ and Cl-, K+ is uphill)
  • Recycling of K+ (secretion to keep NKCC2 going) → which way goes K+ depends on relative conductances between apical and basolateral membrane to come out of the cell (apical membrane is very permeable to K+)
  • A bit of paracellular reabsorption because of the leaky tight junctions (a lot less than in PT)

*Basolateral K+ transport provides energy for apical K+ transport

45
Q

What are the cellular mechanisms for K+ transport in the principal vs intercalated cells of the late distal tubule and of the cortical collecting duct? (apical membrane)

A

Principal cells = major site of K+ secretion because of the negative lumen (entry of Na+)
Na permeability of the apical memrbane → more depolarized membrane than basolateral side → K+ diffuses preferentially into the lumen

Intercalated cells → K+/H+ ATPase, more reabsorption in low K+ diets

46
Q

What are the cellular mechanisms for K+ transport on the basolateral membrane along the kidney?

A
  • Na+/K+ ATPase
  • K+ transporter
  • In some places, leaky tight junctions
47
Q

Which channel is specific for K+ transport from inside to outside the cells in the apical membrane?

A

ROMK (Renal outer medulla potassium channel):
- ROMK1 → apical K+ secretion in the C/M collecting duct
- ROMK2 → TAL K+ recycling + DCT + CCD
- ROMK3 → TAL K+ recycling + DCT

Sturcture:
- N and C-term inside the cells
- 2 TM domains

48
Q

Which are the factors influencing urinary K+ excretion?

A
  1. Dietary intake of K+ → increaes Na/K ATPase activity
  2. Mineralocorticoids → mostly aldosterone
  3. Urinary Na+ excretion → Na entry depolarizes the apical membrane of principal cells of the CD → enhances K+ exit (drugs that lower luminal or apical membrane Na+ reduce K+ secretion)
  4. Urinary flow rate → if low flow rate, when secreted, K+ stays and reduces the driving force (because of high K+ permeability)
  5. H+ balance
  6. Diuretic drugs → cause K+ washing by increase the urinary flow rate (making a gradient/driving force)
  7. Transepithelial potential
49
Q

What happens when there is a big increase in Potassium intake?

A

Increase in K+ intake → increase in plasma [K+] → increase in aldosterone secretion → increase in plasma aldosterone → increase in Na+/K+ ATPase in basolateral membrane of principal cells CCD + increase ROMK activity in principal cells in CCD → increase K+ excretion

50
Q

How does alkalosis and acidosis affect K+ balance in the kidney?

A

K+/H+ Antiport
Alkalosis → enhanced K+ secretion by the CCD:
- Stimulating the basolatral Na/K ATPase
- increasing apical membane K+ permeability

Acidosis → decreased K+ secretion:
- Shift of K= from ICF → ECF under acidosis → Exacerbates hyperkalemia

51
Q

What is the effect of licorice on on Na reabsorption and K secretion?

A

Normally in circulation, high levels of corticosteroid and high levels of mineralocorticoid → receptor not good at differentiating between both, but cortisol is changed into inactive cortisone so can’t bind to MR

Licorice has glycyrrhizin → inhibits 11 beta-HSD 2 which normally turn cortisol into inactive cortisone (can’t bind MR)
So more cortisol can bind mineralocorticoid receptor → more Na reabsorption and K secretion

PHGY 312 (14 decks)

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