Role of the Kidneys in Acid/Base Balance

Question 1

What determines pH?

Answer 1

Concentration of H⁺

pH = -log [H⁺]

Question 2

What is a normal range for pH?

Answer 2

7.35 to 7.45

Question 3

True or False: Concentration of H⁺ in blood at a normal pH is much lower than other things that are in the blood.

Answer 3

True. (despite the small concentration, they are very powerful)

at a pH of 7.40, [H⁺] is 40 nmol/L or 0.00004 mmol/L

Question 4

True or False: There is less bicarbonate than protons in blood.

Answer 4

False.

There is about a million times greater concentration of bicarbonate than protons in blood.

protons is about 40 nmol/L or 0.00004 mmol/L

bicarbonate is 24 mmol/L

Question 5

Why is it important to keep H⁺ concentration controlled in a tight range?

Answer 5

Excess H⁺ will bind to important compounds (proteins) and affect protein charge, shape, and function

Question 6

What is the difference between acidemia and acidosis? alkalemia and alkalosis?

Answer 6

Acidemia is an increase in concentration of H⁺ in the body and acidosis is the process in which there is an addition of H⁺ to the body (respiratory acidosis with increases in P_CO2 and metabolic acidosis with decreases in HCO₃^-)

Alkalemia is a decrease in concentration of H⁺ in the body and alkalosis is the process in which there is a subtraction of H⁺ from the body (respiratory alkalosis with decreases in P_CO2 and metabolic alkalosis with increases in HCO₃^-)

Question 7

Typically, generation of organic acids is equal to utilization/elimination. What are 2 exceptions that we learned about having to do with incomplete oxidation of carbohydrates or fat?

Answer 7

1. With hypoxia, glucose is incompletely oxidized and causes acidosis.
2. With lack of insulin, triglycerides are incompletely oxidized and causes acidosis.

Question 8

The kidney plays a role in acid/base balance primarily by handling _____ acids that come from _____ and _____.

Answer 8

Non-volatile, protiens, nucleic acids

Question 9

True or False: The metabolism of proteins and nucleic acids generates “nonvolatile” acid that must be eliminated by the kidneys.

Answer 9

True

Question 10

What non-volatile acid is typically formed from consuming protein? how about nucleic acid?

Answer 10

Proteins (sulfur containing amino acids) are metabolized into sulfuric acid (H₂SO₄).

Nucleic acids are metabolized into phosphaturic acid (H₃PO₄).

Question 11

The average westerner consumes _____ mmol of nonvolatile acid daily.

Answer 11

60-70 mmol

Question 12

Nonvolatile acid intake is mostly from _____ in diet

Answer 12

meat

Question 13

The acid forming amino acids and alkali forming amino acids in meat is typically balanced. So, what causes net acid intake when eating meat?

Answer 13

Sulfur containing amino acids are metabolized into sulfuric acid (H₂SO₄)

Question 14

An average western diet consumes 60-70 mmol of nonvolatile acid daily. What would happen to serum H⁺ if the body didn’t have acid/base balancing mechanisms?

Answer 14

Normal [H⁺] is about 0.0001 mol/L. Adding 70mmol to an avg ECF volume of 15 liters results in a concentration of 4.7 mmol/L, about 47,000 times normal [H⁺]. pH would be about 2.4

Question 15

What is the primary way that the body handles nonvolatile acid intake to maintain a proper pH?

Answer 15

Buffering. Buffering binds to protons but do not eliminate them.

ECF proteins

• albumin
• immunoglobulins

Other buffers

• amines
• carboxylates
• histidines
• Bone

Question 16

Buffering of acid helps the body to maintain proper pH when ingesting non-volatile acids. However, buffering doesn’t eliminate the acids. What system helps to eliminate these acids through the lungs?

Answer 16

Bicarbonate buffering system (BBS)

H⁺ + HCO₃^- → H₂CO₃ → CO₂ + H₂O

CO₂ is then removed by the lungs via expiration.

Question 17

Does a high CO₂ or low CO₂ level drive the function of the bicarbonate buffering system for elimination of H⁺ from the body? How about high or low blood pH?

Answer 17

H⁺ + HCO₃^- → H₂CO₃ → CO₂ + H₂O

Low CO₂. With a low CO₂, the reaction is driven to the right which takes H⁺ from the body and eliminates through the lungs in the form of CO₂.

Low pH. With a low pH, there is a high H⁺ which wil also drive the reaction to the right. Acidemia stimulates ventilation which lowers P_CO2

Question 18

At the tissue level, O₂ consumption results in an addition of CO₂ to the capillaries. However, there are 2 conditions that will result in an accumulation of CO₂ in the tissues instead of being eliminated. What are these conditions? Why is this bad?

Answer 18

1. Rise in metabolic rate without a proportional increase in blood flow
2. Decrease in blood flow without a change/decrease in metabolic rate

Either one of these conditions imparis the function of the Bicarbonate Buffering System because CO₂ builds up and drives the reaction to the left causing less H⁺ to be removed by the system. Excess H⁺ then binds to proteins and disrupts function.

H⁺ + HCO₃^- ← H₂CO₃ ← CO₂ + H₂O

Question 19

What are the 3 tasks of the kidney for acid/base balance?

Answer 19

• Eliminate acid anions
  
  • HSO₄^- and H₂PO₄^- are filtered by the glomerulus and excreted
• Reabsorb all of the filtered bicarbonate
  
  • Freely filtered by the glomerulus and avidly reabsorbed in the proximal tubule (85-90% of it)
• Synthesize/generate new bicarbonate
  
  • Since HCO₃^- is continuously consumed via H⁺ buffering (60-70mmol/day), the kidneys must synthesize/generate 60-70mmol of HCO₃^- daily to maintain HCO₃^- balance.
  • This occurs primarily at the distal tubule by the intercalated cells in the collecting duct.
  • There is only about 360mmol of total HCO₃^- in the ECF so that’s a 5-6 dady supply of bicarbonate if there was no synthesis or generation of HCO₃^-

Question 20

Explain the bicarbonate reabsorption mechanism in the proximal tubules.

Answer 20

Bicarbonate and Na are traveling in the tubule.

Na⁺ is taken into the proximal tubule cell in exchange for a H⁺. This is done through an Na⁺/H⁺ exchanger on the apical membrane of the proximal tubule cell.

The H⁺ reacts with HCO₃^- to form H₂CO₃. The H₂CO₃ is turned into water and carbon dioxide by the carbonic anhydrase enzyme.

The carbon dioxide and water are absorbed into the proximal tubule where they are turned back into H₂CO₃ by carbonic anhydrase which splits back into H⁺ and HCO₃^-. The H⁺ is used for the exchanger mentioned above to bring in more Na⁺ and the HCO₃^- is taken across the basolateral membrane with Na⁺ by a cotransporter.

If you follow the H⁺s, you can see that they leave the cell and come back in a cycle. However, the bicarbonates are being taken in from lumen and put into the blood (bicarbonate reabsorption).

Question 21

True or False: There is a net loss of ECF HCO₃^- due to the proximal tubule bicarbonate reabsorption.

Answer 21

FALSE. There is no net gain or loss of ECF H⁺ or HCO₃^-. There is no change in acid-base balance.

Question 22

What is proximal renal tubular acidosis? How does this happen?

Answer 22

Proximal renal tubular acidosis (RTA) happens if the proximal tubule bicarbonate reabsorption system is impaired. If bicarbonate is not reabsorbed, it is eliminated. This causes acidosis.

Question 23

How does renal bicarbonate synthesis/generation work?

Answer 23

Carbon dioxide from the peritubular capillaries enter the intercalated cells where they join with water to create H₂CO₃ (via carbonic anhydrase). H₂CO₃ then dissociates into H⁺ and HCO₃^-. The H⁺ is secreted into the lumen of the collecting duct by ATPase and the HCO₃^- is exchanged for Cl^- across the basolateral membrane by a bicarbonate/chloride exchanger.

This results in H⁺ being secreted and HCO₃^- being reabsorbed.

Note that this mechanism only happens if there isn’t HCO₃^- in the tubular lumen. As long as there is bicarbonate in the tubular lumen, bicarb will be reabsorbed but not synthesized

Question 24

Is more bicarbonate reabsorbed or synthesized in the nephrons?

Answer 24

Reabsorbed. Daily reabsorption is about 4,320 mmol while daily synthesis is only 60-70 mmol.

Compared to synthesis, reabsorption requires 60 times the capacity of exchangers, channels, and proton pumps.

Question 25

True or False: Essentially no bicarbonate synthesis can take place until bicarbonate reabsorption is complete.

Answer 25

True

Question 26

True or False: Urine has an acid buffering system so that it doesn’t get too acidic.

Answer 26

True.

Without a buffering system, urine would be about 1.4 pH. This would be way too toxic for the epithelial cells lining the urinary tract and secretion of H⁺ would be energetically expensive/impossible.

With a buffering system, the lowest urine pH is around 4.5.

Question 27

What are the two main urinary buffering systems to make sure urine pH doesn’t get too low?

Answer 27

Titratable acid and ammonia trapping

Question 28

What is titratable acid and how does this maintain a normal urine pH?

Answer 28

When H⁺ are secreted from the intercalated cells, they react with HPO₄^2- to form H₂PO₄^- and excreted. The protons are also buffered by creatinine and urate.

About 30-40mmol of protons are titrated this way.

Question 29

What is ammonia trapping?

Answer 29

In the proximal tubule cells, glutamine is converted to ammonia (NH₃) by glutaminase. Ammonia freely passes across the apical membrane ending up in the tubular lumen. In the distal part of the nephron, H⁺ that is secreted from intercalated cells combines with the ammonia to form ammonium (NH₄⁺).

Ammonia has a very high affinity for protons so it is favorable to turn into ammonium. While ammonia can freely diffuse around, once it turns into ammonium it cannot permeate the membranes so it is trapped in the urine and excreted.

Question 30

What is ammoniagenesis and where does it happen?

Answer 30

Ammoniagenesis is the generation of ammonia. It happens in the proximal tubule cells where glutamine is metabolized into ammonia (NH₃) and bicarbonate. The ammonia ends up in the tubular lumen and the bicarbonate is reabsorbed into the peritubular capillary.

Question 31

When can ammoniagenesis increase?

Answer 31

Ammoniagenesis typically titrates around 40 mmol of protons under normal conditions. When there is a high concentration of protons in the proximal tubule cells (during chronic acidosis or hypokalemia), ammoniagenesis can increase and titrate up to 200 mmol of protons per day.

Question 32

True or False: Titratable acid excretion can increase in situations of acidosis

Answer 32

False.

Titratable acid excretion is relatively stable and has to do with the amount of protein ingested in a diet. It is the ammoniagenesis that can increase in situations of chronic acidosis.

Question 33

How do you calculate net acid excretion (NAE)?

Answer 33

NAE = (NH₄⁺ excretion) + (Titratable acid excretion) - (HCO₃^- excretion)

About 40-50% of NAE is typically titratable acid. This is a relatively constant depending on protein intake of diet.

About 50-60% of NAE is ammonium excretion. This can increase with an increase in ammoniagenesis in response to chronic metabolic acidosis.

Bicarbonate excretion is essentially zero in normal circumstances.

Question 34

How do the 3 factors of NAE change in chronic metabolic acidosis?

1. NH₄⁺
2. Titratable acid excretion
3. Bicarbonate excretion

Answer 34

NH₄⁺ excretion increases because ammoniagenesis increases to titrate more acid.

Titratable acid excretion is unchanged because it is relatively constant and depends on protein ingestion in diet.

Bicarbonate excretion remains at zero.

Question 35

How do the 3 factors of NAE change in chronic metabolic alkalosis?

1. NH₄⁺
2. Titratable acid excretion
3. Bicarbonate excretion

Answer 35

In states of chronic metabolic alkalosis, bicarbonate excretion increases because the body has an excess of bicarbonate in alkalosis and needs to eliminate the excess. Bicarbonate excretion can go up to 80 mmol/day which happens by decreased bicarbonate reabsorption.

NH₄⁺ and titratable acid excretion both decrease because there is no need to titrate as much acid in a state of alkalosis.

Question 36

Upregulation/downregulation of apical and basolateral transporters is dependent on ECF _____ and _____

Answer 36

pH and CO₂ levels

Question 37

In states of acidosis, what happens to ECF [H⁺] and [HCO₃^-]? How are apical and basolateral transporters regulated in reaction to acidosis?

Answer 37

In acidosis (both metabolic and respiratory),

ECF [H⁺] increases and [HCO₃^-] decreases.

This causes an increase in apical H⁺ and basolateral HCO₃^- transporters so that more protons can be eliminated and more bicarbonate can be reclaimed.

Question 38

In states of alkalosis, what happens to ECF [H⁺] and [HCO₃^-]? How are apical and basolateral transporters regulated in reaction to acidosis?

Answer 38

In states of alkalosis (both respiratory and metabolic),

ECF [H⁺] is decreased and [HCO₃^-] is increased.

This results in decreased apical H⁺ transporters and basolateral HCO₃^- transporters. This causes less H⁺ to be eliminated and less HCO₃^- to be reclaimed.

Question 39

Understand this flow chart of metabolic acidosis

Question 40

Explain this flow chart for the renal response to respiratory acidosis

Question 41

How can hypokalemia cause metabolic alkalosis?

Answer 41

When there is decreased ECF [K⁺], K⁺ will shift out of cells into the ECF. This is done in exchange for H⁺. So, you end up with higher intracellular H⁺ in all cells, including the renal tubule cells.

This increases ammoniagenesis which allows for more H⁺ trapping and excretion.

In the intercalated cells, the cells will preferentially reabsorb K⁺ in exchange for H⁺. This is done by an H⁺/K⁺-ATPase on the apical membrane of the intercalated cells. (Remember that in the intercalated cells, when H⁺ is secreted, HCO₃^- is reclaimed).

This all results in more proton secretion/excretion and more HCO₃^- synthesis which causes metabolic alkalosis. Hypokalemia is often associated with metabolic alkalosis but this isn’t always the case.

Question 42

How can metabolic alkalosis cause hypokalemia?

Answer 42

Question 43

True or False: In hyperkalemia, K⁺ shifts into cells from the ECF

Answer 43

True

Question 44

Hypokalemia is related to metabolic alkalosis. Hyperkalemia is related to metabolic acidosis but to a lesser degree. Explain the mechanism and why it’s not such a clear cut relationship.

Answer 44

Potassium shifts into cells from the ECF in exchange for protons which shift out of the cells (this happens in all cells including those of the renal tubules). Less intracellular protons are available in the renal tubules for secretion. This decreases ammoniagenesis which decreases ability for H⁺ trapping and excretion. Less H⁺ secretion/excretion results in less HCO₃^- synthesis.

However, this is not a clear cut relationship because hyperkalemia also stimulates aldosterone. Aldosterone increases H⁺ secretion and HCO₃^- synthesis. This causes a counteractive effect so we don’t always see metabolic acidosis from hyperkalemia.