5 - Acid Base Regulation by the Kidney I Flashcards
What is a buffer?
A buffer is a solution of a weak acid and its conjugate base - resists changes in pH
What is the major buffer system in the blood?
The bicarbonate buffer system is the major buffer system operating in the blood
Hemoglobin also plays important role here
What equation allows you to calculate the degree of dissociation of a weak acid in a given pH?
The Henderson-Hasselbalch equation allows one to calculate the degree of dissociation of a weak acid at a given pH
What is the H-H equation?
pH = pKa + log ([A-]/[HA])
where HA is the weak acid and A- is the conjugate base
What is the H-H equation for the bicarbonate buffer system specifically?
pH = 6.1 + log ([HCO3-]/(0.03)xPCO2)
KNOW THIS ***
Why is acid base balance needed in the first place?
Typical American diet generates 50 - 100 mmol of H+ per day ***
- Oxidation of nutrients generates CO2
- Oxidation of methionine/cysteine
- Some phosphate-containing compounds
- Metabolism of glutamate/aspartate
Describe the formation of carbonic acid increasing pH
- Oxidation of nutrients generates CO2
- This forms carbonic acid
- This is volatile and needs to be removed as CO2 by lungs
Describe the formation of sulfuric acid increasing pH
- Oxidation of methionine/cysteine and other sulfur-containing compounds form sulfuric acid
- This is non-volatile
Describe the formation of phosphoric acid increasing pH
- Some phosphate-containing compounds form phosphoric acid
- This is non-volatile
Describe what glutamate and aspartate do to pH
Metabolism of glutamate/aspartate and use of certain organic anions generates base
Describe the state of respiratory acidosis
- hypoventilation (not blowing off enough CO2)
- increased PCO2
- point on normal buffer slope below pH 7.4
Describe the state of respiratory alkalosis
- hyperventilation (blowing off too much CO2)
- decreased PCO2
- point on normal buffer slope above pH 7.4
Describe the state of metabolic (kidney) acidosis
- loss of HCO3- (too much base lost in the urine)
- point on 40 torr isobar below pH 7.4
Describe the state of metabolic alkalosis
- increase in HCO3- concentration (not losing enough base in the urien)
- point on 40 torr isobar above pH 7.4
What is compensation in terms of acid base balance?
Changes in one buffer component lead to compensatory changes in the other component
- ratio of HCO3- to PCO2 remains close to normal
- pH remains close to normal
Describe respiratory compensation
- hypo or hyperventilation regulates PCO2
- rapid (hours)
Describe renal compensation
- regulation of HCO3- concentration
- regulation of H+ excretion
slow (days)
How do the kidneys carry out this pH regulation function?
- Kidneys regulate H+ excretion and HCO3- reabsorption
- Kidney must dispose of 50 - 100 mmol of H+ per day
How does H+ leave in the urine?
Cannot leave as free H+ (urine pH typically 5.5 to 6.5)
H+ ions removed by
- binding to filtered buffers (H2PO4-)
- binding to NH3 (NH4+)
Describe the elimination of HCO3- in the urine
* Elimination of HCO3- in urine is equivalent to adding H+ to the body*
Cannot eliminate the H+ load unless virtually all filtered HCO3- is reabsorbed
Describe the secretion of H+ by renal tubule cells into the tubular lumen in the proximal region
This process is called proximal acidification
- The sodium-potassium ATPase, present in the basolateral membrane of proximal tubule cells, generates a transmembrane sodium electrochemical gradient.
- The energy of this sodium gradient is used to drive efflux of protons into the tubular lumen via an H+/Na+ exchanger.
- An H+-transporting ATPase is also present, which contributes to H+ secretion but the major player is the H+/Na+ exchanger.
Describe the secretion of H+ by renal tubule cells into the tubular lumen in the distal region
This is called distal acidification
- An H+-transporting ATPase is found in the plasma membrane of the intercalated cells of the collecting duct.
- This transporter is responsible for active secretion of H+ into the tubular lumen.
- * In response to low pH, cytoplasmic vesicles that contain the H+-transporting ATPase fuse with the luminal membrane (they insert into the wall), increasing the cell’s ability to secrete H+*
- ** Conversely, an alkali load (high pH) stimulates recycling of these transporters from the luminal membrane back to cytoplasmic vesicles **
So, what happens in distal acidification in response to LOW pH?
Insertion of ATPase into luminal membrane stimulated by low pH
And, what happens in distal acidification in response to HIGH pH?
High pH stimulates recycling of ATPase back to the cytoplasm
Describe the resorption of bicarbonate in a normal, healthy individual
- filters ~ 4300 mmol HCO3- per day (~ 260 g or 0.57 lb)
- virtually ALL bicarb is reabsorbed
- 90% reabsorbed in proximal tubule
- 10% reabsorbed in collecting duct system
How is the bicarb reabsorbed?
Reabsorption is not by simple transport of HCO3- back from the tubular lumen into the filtrate
It is more complicated…
Describe how bicarbonate is reabsorbed in the proximal tubule
- H+ secreted into tubule lumen
- Reacts with HCO3- in filtrate, forming carbonic acid
- Carbonic anhydrase converts carbonic acid to H2O and CO2
- H2O and CO2 diffuse into renal tubular cell
- Carbonic anhydrase converts H2O and CO2 to carbonic acid
- Carbonic acid dissociates, H+ exported to tubule lumen and HCO3- exported to blood
What is the net effect of bicarbonate reabsorption in the proximal tubule?
Net effect: movement of NaHCO3 FROM the filtrate TO the blood
Describe the reabsorption of bicarbonate in the collecting duct
Slightly different system operates in the collecting duct
Very similar to the proximal tubule, but in the collecting duct, a chloride/bicarbonate antiport system appears to operate (rather than the sodium/bicarbonate co-transporter seen in the proximal tubule)
So what are the types of transporters in the proximal tubule and collecting duct for bicarbonate reabsorption?
Proximal tubule = sodium/bicarbonate co-transporter
Collecting duct = chloride/bicarbonate antiport system
Describe the process of active bicarbonate secretion into the filtrate
This is a bit of a side note, FYI
Kidney actively secretes bicarbonate when needed
- B-type intercalated cells of collecting tubule
- polarity of membrane transporters can be reversed
- becomes important during metabolic alkalosis
What is the “limiting urine pH”?
In the proximal tubule…
- [H+] increased 4-fold from 4 x 10-8 mol/L to 1.6 x 10-7 mol/L
In the collecting duct…
- H+ translocating ATPase stimulated by acid load
- This increases [H+] further to 4 x 10-5 mol/L maximum value
- This corresponds to limiting urine pH of 4.4 ***
- H+ translocating ATPase now inhibited ***
NOTE: the limiting urine pH is therefore a [H+] of 0.04 mmol/L
Daily acid load from normal diet is 50 - 100 mmol, which would require 1250 - 2500 liters of urine/day and obviously this does NOT happen
What is the value of “limiting urine pH” again?
Limiting urine pH of 4.4 or [H+] of 0.04 mmol/L
How does the body accommodate for this?
Excretion of H+ as H2PO4-
Describe the process of excretion of H+ as H2PO4-
- Secreted H+ is buffered in filtrate and the buffer is excreted
- Phosphate typically major non-bicarbonate urinary buffer
- H+ secretion increases [H+] in tubular lumen
- Shifts equilibrium leftward
- This drives formation of H2PO4-, eliminated in urine
What limits the body’s ability to excrete H+ as H2PO4-?
Ability to excrete H+ as H2PO4- limited by…
- amount of HPO42- in filtrate
- requirement of body to retain phosphate
- ~75% filtered phosphate reabsorbed even during acidosis
What is the KEY POINT for the concept of excretion of H+ as H2PO4-?
For each newly-formed H2PO4- excreted in urine…
- One H+ eliminated, and
- One new HCO3- formed and added to the blood***
This contributes to the pH of the blood **
What is titratable acid?
- Measure of H+ excreted in urine as undissociated weak acid (generally H2PO4- most abundant)
How do you determine the titratable acid value?
- 24 hr urine collection
- Measure amount of NaOH required to back-titrate urine pH to 7.4
What is the normal value for titratable acid?
Normal value: ~20 mmol/day
What is the value for titratable acid in the state of acidosis?
Acidosis: ~40 mmol/day
What other weak acids may be quantitatively important in this calculation?
Remember, the main one was H2PO4-
Others include:
- β-hydroxybutyric acid (during ketoacidosis)
- lactic acid (during lactic acidosis)
Note efficiency is a function of the pKa of the weak acid, concentration of the weak acid, and urine pH
- Example: pKa of β-hydroxybutyric acid is ~4.7 but acetoacetic acid is ~ 3.6
Describe the excretion of H+ as NH4+
First step is generation of NH4+ within renal tubule cells
- kidney expresses glutaminase
- converts glutamine to glutamate
- glutamate then converted to α-ketoglutarate by glutamate dehydrogenase
- glutamate metabolism ultimately yields 2 HCO3-
What is the net effect of H+ as NH4+?
Net effect is excretion of protons into the lumen and addition of NEW molecules of HCO3- to the blood
What signals H+ secretion as NH4+ in the urine?
- NH4+ excretion increases rapidly in response to increased urine acidity
- NH4+ reaches maximum in a few days
How does the body compensate to allow this increase capacity to excrete H+ as NH4+
The body compensates fro this increased need for NH4+ excretion by increasing glutamine uptake by kidney/increased glutaminase activity
In severe acidosis, NH4+ production contributes up to 250 mmol/day of new bicarbonate to the blood
What does the rate of H+ secretion depend on?
- Rate of H+ secretion is pH dependent
- Reduced pH activates Na+/H+ antiporter and H+-ATPase
Describe the secretion of H+ in a normal, healthy individual
Healthy individual eating standard Western diet secretes enough H+ to allow reabsorption of most bicarbonate
- some titratable acid (mainly H2PO4- excreted)
- some NH4+ secreted
Describe the secretion of H+ in the state of acidosis
- H+ secretion increased
- all HCO3- reabsorbed
- substantial titratable acid excreted
- NH4+ production increased
- –> increased glutamine uptake/glutaminase activity
- –> increased NH4+ excretion in urine
Describe the secretion of H+ in the state of alkalosis
- H+ secretion insufficient to allow HCO3- reabsorption
- HCO3- is secreted in urine
- B-type intercalated cells of collecting duct actively secrete bicarbonate into tubular lumen
- no titratable acid or ammonium ions excreted in urine
