Renal mechanisms of acid secretion Flashcards
1
Q
Tubular acid secretion
A
- Body produces metabolic acidic waste, must excrete about 60mEq/day thru kidneys
- 2 different functions of tubule acid secretion (same as HCO3- retention)
- Reabsorb filtered HCO3- to the blood to buffer
- Form new HCO3- in kidney to buffer the blood
- Limitation: transporters responsible for acid secretion (NHE and H ATPase) stop working when tubular lumen pH falls below 4.4 (b/c of steep uphill gradient)
2
Q
Bicarb reabsorption in PT/TAL vs intercalated cells of CD 1
A
- In PT and TAL HCO3- is reabsorbed by being converted to CO2 in lumen by CA (requires a secreted H+), crossing the apical membrane and being converted back into HCO3- by CA inside the cell
- The HCO3- is transported across the basolateral membrane by Na-bicarb cotransporter (NBC) which uses the bicarb gradient
- In the CD, there is no CA in the lumen (HCO3- to CO2 rxn is much slower), and the transporter that brings HCO3- into the blood on the basolateral membrane is a HCO3-/Cl- anti porter
3
Q
Bicarb reabsorption in PT/TAL vs intercalated cells of CD 2
A
- For all of this to happen there must be H+ secretion via NHE and H+ ATPase (PT/TAL) or H+ ATPase and H/K ATPase (distal nephron)
- Net effect: filtered HCO3- is reabsorbed and returned to circulation but the molecule that is brought over the basolateral membrane is not necessarily the same molecule that is reabsorbed
- Inhibiting CA (acetazolamide) or Na/H exchanger (amioride) will inhibit reabsorption of NaHCO3 which reduces isoosmotic H2O reabsorption and leads to diuresis and loss of NaHCO3
4
Q
Titratable acid formation
A
- Filtered buffers in the tubular fluid can trap secreted H+ and buffer the fall in lumen pH
- Phosphates, sulfates, urate, creatinine can do this
- This helps to maximize the amount of new HCO3- formed, by helping to prevent the lumen pH fall below 4.4 when the secretion of H+ is largely halted
- This capacity is based on the amount of filtered buffers
- More filtered buffers means more bicarb formation (want H+ secretion b/c its required for HCO3- reabsorption and helps facilitate making new bicarb, but too much means pH falls below 4.4 and then H+ secretion stops)
5
Q
Reaction to metabolic acidosis
A
- As blood H+ rises the blood HCO3- falls (becomes CO2), therefore the kidneys try to replenish HCO3- (in two ways)
- To do this the lumen must not fall below 4.4 pH (otherwise H+ secretion and thus HCO3- reabsorption and some HCO3- formation stops), which is done in part by filtered buffers to maximize HCO3- reabsorption/formation
- Tubular epithelial cells (in PT and DT) will make new bicarb from the excess CO2 in them, this ability is limited by the lumen [buffer]
- The CO2 (made in the cell or diffused in from blood) is converted to HCO3- by CA and the HCO3- is brought back over the basolateral membrane to the blood
- New HCO3- can also be formed from glutamine (not dependent on filtered [buffer])
6
Q
Ammoniagenesis
A
- In the mito of PT epithelial cells, glutaminases (activated by fall in pH) metabolize glutamine into NH4+ and aKG
- The NH4+ will be secreted NH3 + H+ or NH4+
- The aKG is further metabolized to glucose and HCO3- (which is reabsorbed)
- This newly formed HCO3- will buffer the fall in blood pH by replacing the lost HCO3-, and its formation is not limited by filtered [buffers] (doesn’t form an H+ so doesn’t need buffer in lumen)
- However, the effective amount of HCO3- created by ammonia genesis corresponds to the amount of NH4+ secreted/excreted
7
Q
Limitation of ammoniagenesis
A
- Formaiton of new HCO3- generated by ammoniagenesis can be consumed in the process of urea production (in liver) if a molecule of NH4+ is reabsorbed with the HCO3-, instead of excreted
- In normal individual, 50% of the NH4+ is reabsorbed and 50% excreted
- This is good b/c its keeps the formation of HCO3- in balance so alkalosis doesn’t occur (half of the created HCO3- is eliminated thru urea production)
- But during acidosis we want to minimize this so the HCO3- formation is maximized
- This is achieved by increasing the amount of NH4+ excreted
8
Q
Handling of NH4+ in LOH and CD 1
A
- Important: NH4+ can use any channel/transporter that K can use
- NH4+ produced in PT by ammoniagenesis is secreted into the lumen via NHE and K channels
- It is reabsorbed in the TAL via NKCC
- In the ISF it can either be in the form of NH4+ or NH3 (depends on pH)
- The [NH4+] in ISF is high in the distal nephron due to the reabsorption at the LOH
9
Q
Handling of NH4+ in LOH and CD 2
A
- NH4+ is thus secreted back into distal nephron lumen thru an NH4+ transporter
- Chronic acidosis increases this transporter activity and abundance in the apical membrane to maximize NH4+ excretion and thus HCO3- formation
- There will be some NH3 in the ISF in the region of the CD, and this must be excreted in order to maximize HCO3- formation
10
Q
Handling of NH4+ in LOH and CD 3
A
- To excrete NH3, it must first be secreted (passive diffusion down gradient) into the lumen of the CD, where is must be trapped (converted to NH4+) to remain there and be excreted
- This process of trapping NH3 depends on the amount of H+ secreted by the CD intercalated cells (H+ ATPase)
- During metabolic acidosis H+ secretion increases which traps more NH3 and thus increases NH4+ excretion
- In the end, urinary NH4+ is a measure of new HCO3- formation during metabolic acidosis
11
Q
Response to metabolic alkalosis
A
- Durin chronic metabolic alkalosis, the kidneys produce an alkaline urine to acidify the bodily fluids
- This is done by intercalated cells in CD which flip their polarity
- Meaning, the H+ ATPase is on the basolateral membrane (instead of apical) and the Cl/HCO3- anti porter (pendrin) is on the apical (instead of basolateral) membrane
- This results in a cell that secretes HCO3- and reabsorbs H+, both actions bring the pH down to normal
12
Q
Effect of RAAS on body pH
A
- RAAS activation stimulates aldo activity
- Aldo increases Na reabsorption (in part) thru ENaC, which increases H+ and K+ secretion
- Thus RAAS can lead to hypokalemia and alkalosis
13
Q
Potassium status and its effect on pH 1
A
- Reciprocal relationship btwn cell [H+] and [K+]
- During hyperkalemia the H+ is displaced from the cell so less is secreted, also meaning less HCO3- is reabsorbed
- Hyperkalemia also decreases NH4+ excretion (leads to acidosis) in 2 ways
- K+ competes w/ NH4+ for transporters, thus more K+ secreted and less NH4+ secreted
- And since K+ displaces H+ from ICF, a reduction of H+ secretion means less NH3 is trapped, more NH3 reabsorbed and less HCO3- formed to buffer pH drop
- Thus hyperkalemia can cause metabolic acidosis
14
Q
Potassium status and its effect on pH 2
A
- But metabolic acidosis can cause hyperkalemia by displacing K+ from cells and reducing its secretion (also opposite of the above happening), thus leading to hyperkalemia
- Hypokalemia can lead to alkalosis (more H+ enters cells as K+ levels fall and thus more H+ secreted)
- Similarly, alkalosis can lead to hypokalemia because as H+ levels drop more K+ enters cell and is secreted (less H+ being secreted b/c want to bring pH up, meaning there is less NH4+ competing w/ K for transporters thus more K secretion)
15
Q
Changes in GFR, ECFV, and CO2 on HCO3- reabsorption
A
- As GFR increases more HCO3- is reabsorbed in PT since the [HCO3-] at end of PT must be constant (deliver more = reabsorb more)
- As ECFV decreases there is release of ATII (RAAS) leading to increased NHE in PT (increases H+ secretion and thus HCO3- reabsorption)
- There is also more ENaC activity in CCD (aldo) leading to increased H+ and K+ secretion
- PCO2 determines [HCO3-] in all cells, so when CO2 increases during respiratory acidosis, the kidneys compensate by increasing H+ secretion and HCO3- reabsorption
