24-02-23 - Renal Acid-Base Balance Flashcards
Learning outcomes
What is an acid?
What is a base?
What is pH a measure of?
How does H+ ion concentration compare to other ions?
What is the formula for pH?
What is the pH of ECF in the body?
What will a pH of >7.5 lead to?
What will a pH of <6.8 lead to?
- Acid: any chemical substance that can donate a proton, H+
- Base (alkali): any chemical substance that can accept a proton, H+
- pH is a measure of H+ concentration, also written as [H+]
- [H+] is much lower than other ions e.g. [H+]ECF = 40 nmol/L vs. [Na+]ECF = 140 mmol/L
- pH = -log [H+]
- The body maintains pH within very narrow ranges
- pH of ECF is maintained between pH 7.35-7.45
- pH > 7.5 leads to loss of consciousness
- pH < 6.8 recovery is near impossible
What can small changes in pH result in?
What are most biologically important substances able to do?
How can this lead altered biological activity?
What are 5 types of pH-sensitive molecules?
- Small changes in pH can have substantial consequences
- Most biologically important molecules can either
1) Donate an H+ (e.g. act as a weak acid)
2) Accept an H+ (e.g. act as a weak base) - The extent to which these groups accept/donate H+ can cause net change in electrical charge and alter biological activity e.g. altered affinity for charged ligand or altered molecular configuration
- 5 types of pH-sensitive molecules:
1) Enzymes
2) Receptors and their ligands
3) Ion channels
4) Transporters
5) Structural proteins
What are 3 ways the body defends against changes in [H+]ECF?
How quickly do they each occur?
How do they each work?
- 3 ways the body defends against changes in [H+]ECF:
1) Chemical acid-base buffer systems of body fluids
* Immediate (seconds)
* Combine with an acid/base to prevent excessive changes in [H+]
* But, they do not eliminate H+ from, or add H+ to, the body – they only keep them “tied up” until re-balanced
2) Respiratory system
* Fast (few minutes)
* Regulates the removal of CO2 (and therefore H2CO3)
3) Kidneys
* Slow (hours to days)
* Eliminates excess acid/base from the body
* Most powerful acid/base regulatory systems
What is a buffer?
What happens if H+ concentration increases.
Describe the formula for the Bicarbonate (HCO3 - ) buffer system (in photo). What is the most important extracellular buffer system?
What regulates CO2 and bicarbonate in the bicarbonate buffer system?
What is the formula for pH using the Henderson Hasselback equation (in picture)?
- A buffer is any substance that can reversibly bind H+
- if H+ concentration increases, more H+ binds to buffer
- Bicarbonate (HCO3 - ) buffer system (in photo)
- The bicarbonate buffer system is the most important extracellular buffer
- Regulation of CO2 is by lungs and regulation of HCO3 – is by the kidneys in the bicarbonate buffer
- Formula for pH using the Henderson Hasselback equation (in picture)
Why is there a net gain of H+ in the body per day?
What would happen if CO2 wasn’t excreted by the lungs?
What happens to the non-volatile acids generated by metabolism?
What must the kidneys then do?
What is the formula for net acid gain (in picture)?
What is the net acid gain for someone weighing 70kg?
- There is a net gain of H+ in the body per day due to metabolism:
1) Generating volatile acids (in picture)
- Volatile acids can form from:
1) The complete oxidation of neutral carbohydrates and fat – forms CO2 and H2O
2) The oxidation of most neural amino acids – forms urea + CO2 + H2O
- CO2 would become an acid if it formed H+ + HCO3 - (volatile acid), but lungs excrete this CO2 (~15,000 mmol/day)
- This means volatile acids are breathed off
2) Generating non-volatile acids (in picture)
- Non-volatile acids can form from:
1) Oxidation of sulphur-containing amino acids – forms Sulphate ions (non-volatile acid)
2) Metabolism of phosphorus containing compounds – forms Phosphate ions (non-volatile acid)
- Non-volatile acids generated by metabolism are neutralised immediately in the ECF by HCO3 –
- HCO3 - must be replenished, this is achieved by the kidneys
- Formula for net acid gain (in picture)
- The net acid gain for someone weighing 70kg is 70mmol/day
How much acid does the kidney excrete under normal physiological circumstances?
What 3 factors is the excretion of non-volatile acid to do with?
- Under physiological conditions, the kidneys excrete an amount of acid equal to the non-volatile acid production
- 3 factors the excretion of non-volatile acid is to do with:
1) Filtration of HCO3 –
2) Secretion of H+ enabling “modified” reabsorption of HCO3 –
3) Formation of new HCO3 –
* Titratable acid excretion
* Ammonium (NH4 +)
How much acid does the kidney excrete under normal physiological circumstances?
What 3 factors is the excretion of non-volatile acid to do with?
How is HCO3 filtered/reabsorbed in the kidney tubules?
How does HCO3- transport in different parts of the nephron differ?
- HCO3- is freely filtered into the kidney tubules and is usually fully reabsorbed, so very little appears in urine
- Transport in the proximal portions of the nephron (e.g. PT and LOH) is different to the regulated transport in the distal nephron (e.g. DCT and CCD)
HCO3 - transport in the PT.
What gradient does HCO3- in the PT couple to?
How is this gradient generated?
What is H2CO3 converted to?
What happens to these products?
- HCO3 - transport in the PT
- HCO3 - couples to the H+ gradient in lumen of the PT to form carbonic acid (H2CO3)
- This gradient is generated by the Na+/H+ exchanger and H+ pump
- H2CO3 is converted to H2O and CO2 via carbonic anhydrase in the brush border membrane
- CO2 diffuses into cell
- H2O enters cell via aquaporin channels (can also travel via paracellular pathway)
HCO3 - transport in the PT.
What happens to CO2 and H2O that enter the cells of the PT?
What happens to the products of this?
- HCO3 - transport in the PT
- The CO2 and H2O that enter the cell are then converted to H2CO3 by intracellular carbonic anhydrase
- H2CO3 is broken down into H+ and HCO3-, with H+ being secreted back across the apical membrane via Na+/H+ exchangers of H+ pumps
HCO3 - transport in the PT.
What happens to HCO3- in the cell?
What is this movement a modified version of?
How does the reabsorbed and filtered HCO3- molecule differ?
Where else in the nephron does reabsorption of HCO3- like this occur?
- HCO3 - transport in the PT
- HCO3- in the cell is extruded across the basolateral membrane via the:
1) Na+/HCO3 - cotransporter
2) HCO3 - /Cl- exchanger - This is a slightly modified version of transcellular transport
- The HCO3 - that is reabsorbed back into the bloodstream is not the same molecule as was filtered
- The cellular mechanism for HCO3 - reabsorption in the TAL is similar
What are the 2 types of intercalated cells seen in the CD used for HCO3- transport?
- 2 types of intercalated cells seen in the CD used for HCO3- transport:
1) Alpha H+ secreting and HCO3- reabsorbing cells (Alpha-IC)
2) Beta HCO3- secreting and H+ reabsorbing cells (Beta-IC)
HCO3 - transport in the CD.
When do the collecting ducts absorb HCO3-.
Describe the 5 steps in the function of the H+ secreting cell (Alpha-IC)
- HCO3 - transport in the CD
- Collecting duct absorbs HCO3 - that has escaped reabsorption in the proximal tubule
- 5 steps in the function of the H+ secreting cell (Alpha-IC)
1) Apical H+ pump secretes H+ which combines with HCO3 –
2) Converted to H2O and CO2, enters cell like in the proximal tubule
3) Once inside, H+ is pumped back across apical membrane
4) HCO3 - is transported across the basolateral membrane by a HCO3 - /Cl exchanger
5) Cl- exits back via basolateral Cl- channel
How do the Alpha and Beta IC of the CD differ in function?
Describe the 5 steps in the functioning of the Beta IC
- The Alpha and Beta IC of the CD function in reverse to each other:
- 5 Steps in the functioning of the Beta IC:
1) HCO3 - is transported across the apical membrane by a HCO3 - /Cl- exchanger
2) Cl- exits via basolateral channel
3) HCO3 - combines with H+ in tubule
4) Converted to H2O and CO2, enters cell like in the proximal tubule
5) Once inside, H+ is pumped across the basolateral membrane towards blood
Does H+ or HCO3- secretion predominate in the CD?
In what situation can the activity of HCO3- be increased?
What is a majority of tubular acid secretion use for?
- Under physiological conditions, H+ secretion (from Alpha IC) in the CD predominates
- The activity of the HCO3 - cell can be increased in response to a metabolic acidosis
- Together, the majority of tubular acid secretion is used to reabsorb the filtered HCO3
Formation of titratable acid.
When will a new portion of HCO3- be produced?
What other buffers can H+ combine with?
How much phosphate is left in the tubule after PT reabsorption?
Why is this buffer favoured? What happens to H+ when HCO3- is reabsorbed?
How much non-volatile acid is then secreted as H+?
How is new bicarbonate formed from this system?
- Formation of titratable acid.
- A portion of new HCO3 - is produced when urinary buffers are excreted as titratable acid
- H+ can interact with buffers other than HCO3 - e.g. phosphate, creatinine
- 10% of phosphate Is still in tubule after PT reabsorption
- Less water and the pH of tubular fluid favours this buffer
- Once HCO3 - reabsorbed, H+ will combine with phosphate, which will buffer and “mop up” the secreted H+ ions
- Only a small part of the excess non-volatile acid can be excreted as H+
- For ever proton that we excrete that phosphate picks, we have gained a free bicarbonate that is reabsorbed into the blood through mechanisms we have covered
- This is called ‘new bicarbonate’
Formation of titratable acid.
What is the second buffer used in tubular fluid?
How is ammonium generated?
What cells can glutamine enter in the nephron?
Where else can it come from?
What is glutamine metabolised to?
What is NH4+ broken down into?
What will this then generate?
- Second buffer system in tubular fluid (used to titrate secreted H+) is ammonia (NH3) and the ammonium ion (NH4 +)
- Ammonium (NH4 +) is generated from metabolism of glutamine
- Some glutamine is filtered, enters cell across apical membrane in proximal tubule, but a majority is transported from the blood into the epithelial cell
- Glutamine is metabolised to NH4 + + HCO3 –
- NH4 + broken down to H+ and NH3 and secreted into tubule
- Newly generated HCO3 - transported across basolateral membrane back into blood
