Bicarbonate

Question 1

Is bicarbonate mainly an intracellular or extracellular anion ? What is its principal function ?

Answer 1

Bicarbonate is mainly an extracellular anion

Buffer buffer of ECF and blood

Question 2

State the equation that guides bicarbonate-acid interactions in the body, describing each element of this equation.

Answer 2

CO2 +H2O ↔ H2CO3 ↔ H+ + HCO3-

• CO2 is regulated by the respiratory system
• CO2 is a volatile acid (can be eliminated by being blown off)
• H+ (non volatile acid) is added to the body by diet and metabolism
• HCO3- is regulated by the kidneys, replacing any used up bicarbonate (and lost in feces each day)

Question 3

Describe, using a mathematical formula, the link between bicarbonate and pH.

Answer 3

pH ∝ (HCO3-) / (pCO2)

Question 4

Based on the following equation:
CO2 +H2O ↔ H2CO3 ↔ H+ + HCO3-

What would happen upon an increase in CO2 (e.g. suboptimal respiration) ?
What would happen upon an increase in metabolic acidemia ?

Answer 4

Shifts it to the right, i.e. more HCO3- and H+

H+ being added to the body in a metabolic acidemia, so uses up bicarbonate. Hence bicarbonate falls so pCO2 has to fall.

Question 5

Define minute ventilation. What would happen to pCO2 if minute ventilation decreased ? to HCO3- ?

Answer 5

Minute ventilation = tidal V x resp rate

If minute ventilation decreases, paCO2 will increase, so HCO3- will increase as well (latter in order to maintain pH)

Question 6

What kind of pathology is present if HCO3- and pCO2 move in opposite directions ?

Answer 6

Mixed acid base pathology

Question 7

Identify the main overall actions performed by the kidney.

Answer 7

• Bicarbonate filtration (at the glomerulus) 
• Bicarbonate reabsorption
• Bicarbonate regeneration by: 
– Titratable acid excretion
– Ammonium excretion

Question 8

Which of titratable acid excretion, or ammonium excretion is the larger component of bicarbonate regeneration ? the more constant one ?

Answer 8

Titratable acid excretion is the more constant one
Ammonium excretion is the larger component (Accounts for 2/3, versus 1/3 for titratable acid excretion. Can increase in times of need such as metabolic acidemia)

Question 9

Describe the change in pH along the tubule.

Answer 9

Starts at pH 7.4 at the beginning of PT. As fluid progresses along lumen, becomes more acidic.

pH 6.9 in thick descending limb

pH 4.5 in collecting tubules

Question 10

What is the per minute rate of glomerular filtration in a normal individual ? daily rate ?

Answer 10

120-125 mL/min

180 L /day

Question 11

What is the normal plasma concentration of bicarbonate ?

Answer 11

Normal plasma bicarbonate 24mmol/l

Question 12

How much of bicarbonate is filtered at Bowman’s capsule ?

Answer 12

Freely filtered (all of it)

Question 13

Is bicarbonate mainly reabsorbed or not ? If so, where ?

Answer 13

Vast majority is reabsorbed

• 85-90% of filtered bicarbonate is reabsorbed around the proximal convoluted tubule
• Remaining 10-15% of filtered bicarbonate is reabsorbed in DT and Collecting Tubules

Question 14

Which processes of reabsorption are common to both sites of bicarbonate reabsorption (PT on the one hand, and DT and Collecting Tubule on the other) ?

Answer 14

• Apical membrane is impermeable to bicarbonate.
• Bicarbonate in the tubular lumen therefore combines with H+, which forms CO2 + H2O.
• CO2 is freely diffusable, gets into cell, combines with H20 and carbonic anydrase to form HCO3- + H+ (quickly thanks to enzyme)
• HCO3- then gets into blood whilst H+ gets back in tubular lumen

Question 15

Describe the process of proximal reabsorption of bicarbonate (specific to PT).

Answer 15

• In brush border of PT, carbonic anhydrase helps conversion of HCO3- + H+ into CO2 + H2O
• CO2 diffuses into renal tubule cell, combines with water in a reaction catalysed by carbonic anhydrase to form HCO3- + H+
• H+ transported back out into tubular lumen, through secondary active transporter (H+ Na+ exchanger, uses diffusion of Na+ into cell down its concentration gradient to transport H+ out)
• Na+ K+ ATPase (2 K+ in, 3 Na+ out) on the basolateral membrane is the driver to keep cell empty of sodium to create this concentration gradient
• Na+ HCO3- cotransporter on basolateral membrane then combines 1 Na+ out and 3HCO3- out

Question 16

Describe the process of distal reabsorption of bicarbonate (specific to DT/Collecting Tubule).

Answer 16

• Conversion of HCO3- + H+ into CO2 + H2O in tubular lumen (WITHOUT Carbonic Anhydrase, slower process)
• CO2 diffuses into renal tubule cell, combines with water in a reaction catalysed by carbonic anhydrase to form HCO3- + H+
• Distally in tubule, urine much more acidic, i.e. more H+ in tubular lumen, so going along much less steep concentration gradient (if it were to diffuse out of the cell back into tubular lumen) so using ATP (H+ ATPase).
• Bicarbonate transported into blood through HCO3- Cl- exchanger

Question 17

Why is bicarbonate regeneration necessary ?

Answer 17

• Acid is continually produced
• Protons consume bicarbonate (buffering system)
• This bicarbonate must be regenerated
• Bicarbonate regeneration will raise (bicarb) in the renal vein to a level higher than in the artery.

Question 18

Describe the process of titratable acid excretion.

Answer 18

-H+ ion inside the cell, transported out into tubular lumen through Na+ H+ exchanger (secondary active transport, enabled by Na+ K+ ATPase on basolateral membrane creating steep Na+ concentration gradient)
-Instead of binding with bicarbonate ion, H+ binds to non bicarbonate buffer, mainly phosphate
-Phosphate exists in two forms: monoprotic and diprotic forms. Upon combination with H+, monoprotic form converted into diprotic form, essentially trapping
H ion in the urine, so it cannot escape back.
-CO2 is being produced inside cell by normal metabolism and bicarbonate into blood, combining with H2O in a reaction catalysed by carbonic anhydrase to form H+ (to which the aforementioned happens), and HCO3-, which is transported out using Na+ HCO3- cotransporter.

Question 19

How does phosphate get into the lumen, in titratable acid excretion ?

Answer 19

By filtration just like bicarbonate (and just like other non-bicarbonate buffers)
Phosphate in tubular lumen comes from diet (e.g. chocolate, pheasant)

Question 20

State the equation for the combination of the monoprotic form of phosphate with H+.

Answer 20

H+ + HPO4(2-) → H2PO4-

Question 21

How does different parts of the tubule affect the equation: H+ + HPO4(2-) → H2PO4-

Answer 21

At start of PT, pH 7.4, 80% monoprotic form
As progress through tubule into more acidic territory, more H+ so shifts equation to the right, increasing amount of diprotic form

Question 22

Identify non-bicarbonate buffers in urine.

Answer 22

• Phosphate (main one)
• Urate
• Creatinine
• Beta-hydroxybutyrate (ketone produced in diabetic ketoacidosis)

Question 23

Describe the process of ammonium excretion.

Answer 23

• Glutamine is produced by liver, gets to kidney via bloodstream
• In academia, increased production by liver, and take up by kidney increases
• Inside cell, glutamine metabolised into alpha ketoglutarate (AKG2-), with side product of ammonium ion which is excreted into tubular lumen via NH4+ Na+ exchanger (same exchanger as Na+ H+ exchanger)
• AKG2- + H+ (protons (and bicarbonate) obtained from reaction of CO2 with H2O catalysed by carbonic anhydrase) results in CO2 + H2O (or glucose)
• Bicarbonate is transported into blood via HCO3- Na+ cotransport (3 bicarbonates out and 1 Na+ out)
• Powerhouse still present to maintain low Na+ and high K+ inside the cell, which drives excretion of ammonium

Overall result of this process is regeneration of bicarbonate, and ammonium excretion.

Question 24

Where in the kidney does ammonium excretion mainly occur ?

Answer 24

Mainly in PT

Question 25

Is titratable acid excretion constant ? ammonium excretion ?

Answer 25

* Titratable acid excretion is relatively constant (because dependent on phosphate in the diet) * Ammonium excretion can increase markedly (in times of need)

Question 26

When does renal compensation occur ?

Answer 26

In a primary respiratory disorder renal compensation occurs E.g. in COPD (CO2 increased), kidneys compensate by taking that normal bicarboante level at above 24 mmol/L, up to thirties

Question 27

Describe the changes and compensation that occur as a result of respiratory acidemia.

Answer 27

1. Rise in pCO2 (freely diffusable so can get into renal tubular cells and cause acidemia) 2. Parallel change inside the renal tubule cells 3. Intracellular acidaemia 4. Increases uptake and use of glutamine (metabolised to make new bicarbonate) and hence ammonium excretion 5. Increasing bicarbonate regeneration 6. Low intracellular pH increases tubular proton secretion (steeper concentration gradient, so can get transported out of the cell into urine) and ensures optimum reabsorption of bicarbonate

Question 28

Describe the changes and compensation that occur as a result of respiratory alkalemia.

Answer 28

1. Fallin pCO2 2. Parallel change inside the renal tubule cells 3. Intracellular rise in pH 4. Proton secretion falls, so: 5. Bicarbonate reabsorption falls (not enough protons in the urine to combine with the bicarbonate, so bicarbonate just gets excreted)

Question 29

Identify factors which increase bicarb reabsorption and regeneration.

Answer 29

• Increasing PCO2 • Increasing H+ (anything that causes acidemia will increase uptake of glutamine and increase reabsorption and maximise regeneration) • Decreasing ECF volume • Increasing angiotensin ll (also stimulated by falls in ECF volume) • Increasing aldosterone • Hypokalaemia (K+ is an intracellular ion and main reserves are inside cell, so if EC potassium drops, K+ inside the cell goes outside the cell. Again, renal tubular cell interprets that as an acidemia)

Question 30

Identify factors which decrease bicarb reabsorption and regeneration.

Answer 30

* Decreasing PCO2 * Decreasing H+ * Increasing ECF volume * Decreasing angiotensin ll * Decreasing aldosterone * Hyperkalaemia

Question 31

Identify a treatment option for altitude sickness.

Answer 31

Carbonic anhydrase inhibitors, encourage loss of bicarbonate (pomegranate is a source of naturally occurring carbonic anhydrase inhibitor)

Question 32

Explain how decreasing ECF volume / increasing angiotensin ll affect renal bicarbonate handling.

Answer 32

Decreasing ECF volume / increasing angiotensin ll * Stimulates sodium reabsorption * Stimulates activity of Na / H exchange mechanism * Ratio bicarb / H+ in tubular lumen falls * Excess H+ in the tubules * Bicarb fully reabsorbed & NEW bicarb formed

Question 33

Describe the possible effects of impairment in kidney function of bicarbonate handling.

Answer 33

♪ AKI (acute kidney injury) and CKI (chronic kidney injury) ♪ Damage to glomerulus and tubule ♪ Will result in metabolic acidemia ♪ Decrease in ammonium secretion by tubule (remaining healthy glomeruli cannot escalate ammonium secretion enough to counteract damaged glomeruli, so results in metabolic acidemia)

Question 34

What are the most common causes of chronic kidney disease ?

Answer 34

Hypertension and Diabetes Mellitus

Question 35

Define Renal Tubule Acidosis.

Answer 35

"A metabolic acidosis resulting from impairment of the reabsorption of bicarbonate by the renal tubules, characterized by low plasma bicarbonate and high plasma chloride"

Question 36

What are the main types of Renal Tubular Acidosis ? State the main characteristic of each.

Answer 36

♠ Type 1 (AKA distal RTA)- Lowers capacity to conc H+ in distal tubule ♠ Type 2 (AKA proximal RTA)- Impairs prox reabsorption of bicarbonate ♠ Type 4 (AKA hyperkalaemic RTA)- Caused by reduced aldosterone. Inhibits NH4+ production

Question 37

For type 1, 2, and 4 RTAs, state: - Urine pH - Plasma K+ - GFR - Plasma bicar

Answer 37

TYPE 1 RTA (DISTAL RTA): - Urine pH: Above 5.5 - Plasma K+: Usually low - GFR: normal - Plasma bicar: < 10mmol/l TYPE 2 RTA (PROXIMAL RTA): - Urine pH: variable - Plasma K+: Usually low - GFR: normal (but if kidney unable to reabsorb filtered bicarbonate, you will get an acidemia, so plasma bicarbonate is sitting at v low levels) - Plasma bicar: 15-20mmol/l TYPE 4 (HYPERKALAEMIC RTA): - Urine pH: Below 5.5 - Plasma K+: high - GFR: Slightly impaired - Plasma bicar: 15-20mmol/l

Question 38

Which of the RTAs is the most common ?

Answer 38

Type 2 (Proximal RTA)

Question 39

Identify groups of drugs which may lead to impairment in renal function.

Answer 39

ACE inhibitors, Aminoglycosides, contrast media, | NSAIDs, Proton pump inhibitors (latter not as commonly as others)

Question 40

How many days does it take for kidney maximal adaptation ? Why ? Which of these is impaired in renal impairment ?

Answer 40

5-6 days for maximal adaptation because when faced with challenge, kidney starts to produce more glutamine, and renal tubular cells has to take up more glutamine, more ATPase and transporters have to be inserted inside renal tubule membrane. All this requires time. In renal impairment, this function is impaired (principally ammonia excretion)