Renal Handling of K, Ca, PO4

Question 1

What is the normal range of extracellular K⁺ concentration?

Why is the concentration of extracellular K⁺ so tightly regulated?

Answer 1

3.5 - 5.5 mEq/L

small changes in plasma [K⁺] can profoundly affet membrane potential of excitable cells

Question 2

What is the name for an increase in plasma [K⁺]? This has what impact on cells?

What is the name for a decrease in plasma [K⁺]? This has what impact on cells?

What is the name for a decrease in K⁺ excretion?

Answer 2

• increase in plasma [K⁺]
  
  • Hyperkalemia
  • increase in excitability
• decrease in plasma [K⁺]
  
  • Hypokalemia
  • decrease in excitability
• increase K⁺ excretion
  
  • Kaliuresis

Question 3

What progressive ECG responses do you see with increasing hypokalemia?

What progressive ECG responses do you see with increasing hyperkalemia?

Answer 3

• Hypokalemia
  
  • 3.5: low T wave
  • 3:0 low T wave & high U wave
  • 2.5: low T wave, high U wave & low ST segment
• Hyperkalemia
  
  • 7: high T wave
  • 8: high T wave, depressed ST segment, prolonged PR interval
  • 9: auricular standstil, intraventricular block
  • 10: ventricular fibrilation

Question 4

How much K⁺ is secreted or reabsorbed in the proximal tubule?

Answer 4

67% of the filtered load of K⁺ is reabsorbed in the early proximal tubule

a small and variable amount of K⁺ is secreted in the distal part of the proximal tubule

Question 5

How is K⁺ handled in the Loop of Henle?

Answer 5

• ~20% of filtered load of K⁺ is reabsorbed
• Thick ascending limb
  
  • K⁺ is reabsorbed with Na⁺ and Cl^- via the Na-K-2Cl co-transporter
  • since luminal K⁺ is very low, most of the K⁺ diffuses back into the tubular lume (recycyled) to maintain transporter activity
  • very little “net” K⁺ reabsorption

Question 6

What cells in the distal nephron secrete K⁺?

What cells in the distal nephron reabsorb K⁺?

Is there net secretion or reabsorption?

Answer 6

• Distal nephron – collectign tubules and ducts
  
  • Principal Cells (predominate)
    
    • secrete K⁺
  • Intercalated Cells
    
    • reabsorb K⁺
• Normall some net secretion of K⁺
• Net K⁺ reabsorption only occurs when kidneys are conserving K⁺

Question 7

How is K⁺ excretion controlled?

How is K⁺ balance achieved?

Answer 7

K⁺ excretion is controlled by adjusting the rate of tubular K⁺ secretion

K⁺ balance requires that the daily urinary excretion equals the daily dietary intake

Question 8

At the low end of intake, what percent of K⁺ filtered load must be excreted?

What about at the high end?

What is the highest dietary intake of K⁺ where balance can be maintained?

How does this compare the percent of Na⁺ filtered load that is excreted?

Answer 8

Daily filtered load of K⁺ is ~810

Intake 50 mEq/day, 6% FL excreted

Intake 150 mEq/day, 18% FL excreted

Dietary intake as high as 1000 mEq/day, with 125% FL excreted

This compares with daily excretion of only about 0.6% of filtered Na⁺ load

Question 9

How much of the filtered load of K⁺ is reabsorbed in the proximal tubule and Loop of Henle?

Answer 9

90%

so, secretion must predominate over reabsorption int he distal nephron at higher K⁺ intakes to maintain balance

Question 10

Describe the relationship between Pricipal Cells and K⁺

What is the response when plasma K⁺ increases?

Answer 10

• Na⁺- K⁺- ATPase on the interstitial membrane pumps Na⁺ out of the cell (creating a favorable gradient for Na⁺ to enter the cell from the tubular lumen) and K⁺ in the cell.
• Water filled channels (ENAC)
  
  • Na⁺ enters rapidly through these channels producing a lumen negative potential
  • Negative potential drives the paracellular reabsorption of chloride & allows K⁺ to passively leave through luminal water-filled channels (ROMK)
• If plasma K⁺ incrases, K⁺ uptake increases because the Na⁺ - K⁺- ATPase pump is not normally saturated

Question 11

Where are ROMK Cells found?

They are inhibited by what hormone?

Describe their activity under conserving K⁺ loads, normal K⁺ loads, and high K⁺ loads.

Answer 11

• ROMK (Renal Outer Medulla K⁺) channel
  
  • Found in principal cells
  • contribute more to secretion than reabsorption
  • Inhibited by Angiotensin II
• Conserving K⁺ loads - low K⁺ excretion
  
  • ROMK sequestered in intracellular vesicles (closed)
  • BK channels are closed
  • virtually no K⁺ secretion or excretion
• Normal K⁺ loads - Normal K⁺ excretion
  
  • ROMK fuse with membrane & open (secrete K⁺)
  • BK channels remain closed
• High K⁺ loads - high K⁺ excretion
  
  • ROMK activity is maximized
  • BK channels are open

Question 12

What is unique about Type A intercalated cells?

Describe the transporters found on the Luminal membrane.

Describe the transporters on the interstitial membrane.

What is the major funciton of these cells & how is this accomplished?

Answer 12

• No Na-K-ATPase
• Luminal Membrane Transport
  
  • H⁺ actively secreted
  • K⁺ is reabsorbed by K⁺ - H⁺ ATPase
  • BK channel (K⁺ secretion)
• Interstitial Membrane Transport
  
  • HCO₃ - Cl antiport
  • K-Cl co-transport (how K⁺ exits cell & is reabsorbed)
  • Na-K-2Cl pump
    
    • thought to drive the BK channel
• Primarily responsible for K⁺ reabsorption via the K⁺ - H⁺ ATPase & the K-Cl co-transporter
  
  • if need be, the BK channel will open up & provide net secretion of K⁺ under high K⁺ loads

Question 13

Where are BK channels found?

What is their function?

What are they driven by?

Answer 13

• Location
  
  • Type A intercalated cells
  • Principal Cells
• Function
  
  • open & secrete K⁺ when there is need for lots of K⁺ secretion
• Driven by basolateral Na-K-2Cl pump

Question 14

What is the major reason for a rapid increase in plasma K⁺ levels?

How does the body respond to an increase in plasma K⁺ level?

What is the purpose of these responses?

Answer 14

Dietary Intake

• Increased Plasma K⁺
  
  • Enhances Na-K-ATPase activity
  • Insulin
    
    • stimulates release which promotes K⁺ uptake in skeletal muscle, heart and liver
  • Epinephrine
    
    • stimulates release from teh adrenal medulla that promotes K⁺ uptake in muscle and liver bia B₂-receptors
  • Aldosterone
    
    • stimulates the release of aldosterone formt eh adrenal cortex which increases plama K⁺ excretion via principal cells
  • K⁺- H⁺ exchange (passive)
    
    • enhances K⁺- H⁺ exchange in muscles, red cells and liver
• The purpose of these responses is to defend the plasma K⁺ level

Question 15

What will be the response to a primary increase or decrease in extracellular fluid K⁺ concentration?

Where in the body does this occur?

Answer 15

• ECM [K⁺] increase or decrease causes a reciprocal exchange for H⁺
  
  • K⁺ - H⁺ exchanger is used as a rapid “buffer” for changes in plasma [K⁺] at the expense of acid-base status
  • occurs in skeletal muscles, bone, liver, RBC, and kidney tubular cells
• K⁺ secretion is proportional to [K⁺] in tubular cells

Question 16

What is the response to an increased plasma [K⁺}?

What is the response to a decreased plasma [K⁺}?

Answer 16

• Hyperkalemia
  
  • K⁺ enters the cell in exchange for H⁺
  • Hyperkalemia increases K⁺ secretion and causes acidosis
• Hypokalemia
  
  • K⁺ leaves the cell in exchange for H⁺
  • Hypokalemia reduces K⁺ secretion and causes alkalosis

Question 17

What is the response to an increase in plasma [H⁺​]?

What is the response to a decrease in plasma [H⁺​]?

Answer 17

• Acidosis
  
  • H⁺ enters the cell in exchange for K⁺
  • Acidosis reduces K⁺ secretion and causes hyperkalemia
• Alkalosis
  
  • H⁺ leaves the cell in exchange for K⁺
  • Alkalosis increase K⁺ secretion and caues hypokalemia

Question 18

What is the point of the K⁺ / H⁺ ion exchanger?

Answer 18

• Rapid, passive buffer to limit the effect on K⁺ concentration & the deletarious changes in membrane potential

Question 19

Hyperkalemia directly simulates the secreion of what hormone?

What is the effect of this hormone?

Answer 19

• Aldosterone
  
  • from zona glomerulosa cells of adrenal cortex
  • stimulates Na-K-ATPase in collecting tubules
    
    • cellular uptake K⁺
    • luminal membrane K⁺ permeability
    • K⁺ secretion secondary to increased Na⁺ uptake

Question 20

Describe the “aldosterone paradox”

Answer 20

• “Aldosterone Paradox”
  
  • low volume increases Angiotensin II and Aldosterone
    
    • Angiotensin II increases Na⁺ reabsorption in proximal & distal tubule (NCC)
    • More Na⁺ is taken out of early distal tubule, so less Na⁺ reabsorption in collecting ducts, hence little K⁺ secretion in pricipal cells
  • High K⁺ directly stimulates aldosterone release
    
    • stimulates Na⁺ uptake in principal cells (ENaC)
    • Enhances K⁺ secretion and excretion
    • Increases H⁺ secretion & excretion and reabsorption of HCO₃^-.

Question 21

Why are we concerned about hypokalemia & metabolic alkalosis in patients take a loop diuretic?

Answer 21

The loop diuretic decreases Na⁺ reabsorption in the thick ascending limb of the loop of henle, will see a lot of Na⁺ arriving at the distal convoluted tubule. This may drive Na⁺ reabsorption in the Na⁺ / Cl^- cotransporter as well as through the Na⁺ ENAC channels in the principal cells. Consequently, we see a lot of secretion of K⁺ and H⁺ secreted, which can lead to hyopkalemia & metabolic alkalosis.

Question 22

How can increased levels of Aldosterone lead to increased levels of K⁺ excretion?

Answer 22

• Increased levels of aldosterone will:
  
  • Increase K⁺ uptake by tubular cells
    
    • increase intracellular [K⁺]
  • increase Na⁺ reabsorption in distal nephron
    
    • cause a lumen negative potential
  • increase permeability of luminal surface to K⁺ (more K⁺ channels)
• All of which will increase K⁺ secretion in distal nephron and increase K⁺ excretion & maintain a normal balance

Question 23

How does hypervolemia and hyperkalemia impact K⁺ secretion & excretion?

Answer 23

• Load-dependent effect of Na⁺ delivery to the distal tubule
• Hypervolemia (or diuretic use in LOH of DT)
  
  • increased Na⁺ delivery in the distal tubule
    
    • increased Na⁺ absorption by principal cells causes increased K⁺ secretion
      
      • increased K⁺ excretion and hypokalemia
• Hypovolemia
  
  • decreaed Na⁺ delivery in the distal tubule (more absorption in the proximal tubule)
    
    • decreased Na⁺ absorption by principal cells causes decreased K⁺ secretion
      
      • decreased K⁺ excretion and hyperkalemia

Question 24

Describe the mechanism of action for both Loop Diuretics and Thiazide Diuretics

What is the common possible adverse effect of these drugs?

Answer 24

• Loop Diuretics
  
  • block Na-K-2Cl transport in thick ascending limb
• Thiazide Diuretics
  
  • block Na-Cl transport in distal tubule
• BOTH
  
  • increase Na delivering to connecting tubule and collecting duct
  • increase K secretion
  • Increase K excretion
    
    • can lead to K depletion and hypokalemia

Question 25

How can the flow through the nephron influence K⁺ excretion?

Answer 25

• Increased tubular flow (diuresis) results in a “wash-out” of luminal K⁺ that enhances further K⁺ secretion
  
  • _​_no K⁺ adjacent to the luminal membrane that would create a K⁺ gradient
• Decreased flow results in an accumulation of luminal K⁺ and the development of limiting [K⁺] gradients and reduced K⁺ secretion

Question 26

How do non-reabsorbed anions (not Cl^-) in the filtrate affect K⁺ secretion?

Answer 26

• Enhance K⁺ secretion
  
  • the luminal membrane “depolarizes” as Na⁺ enters, creating a negative luminal potential & leading K⁺ to efflux from the cell
  • anions (lactase, SO₄^-, etc) cannot accompany Na⁺ across the luminal membrane
  • there is a compensatory increase in K⁺ and H⁺ secretion to maintain electrical neutrality

Question 27

Draw the flow chart describing Regulation of Plasma K⁺ Concentration and K⁺ Excretion

Answer 27