Renal Regulation H+ and Urea Flashcards
What is the fractional excretion of urea?
What characteristics determine urea’s movement in the nephron?
- 20%
- Urea is freely filtered
- Although small, it is highly polar & does not freely permeate lipid bylayers
- medullary interstitial space contributes to osmotic gradient that allows us to concentrate urine
Describe what happens to urea in each of the following locations:
Proximal tubule
Loop of Henle
Medullary collecting ducts
How does ADH affect this?
- Proximal tubule
- urea is reabsorbed- dependent on the development of a favorable concentration gradient through paracellular paths
- Loop of Henle
- urea is secreted passively down its concentrtion gradient
- Medullary collecting ducts
- urea is reabsorbed by urea transporters (UT)
- ADH
- increases the permeability of MCD to water and urea
- stimulates urea transporter activity in MCD
What is azotemia?
What situations cause this?
- Azotemia
- increased nitrogen in the blood (BUN)
- Can occur with
- decreased GFR (urea production > urea excretion)
- elevated urea production (high protein diet, steroid therapy)
- excessive urea reabsorption in proximal tubule (hypovolemia)
What is uremia?
uremia- used to describe pathologic increases in urea
What clinical presentaitons would indicate a renal cause of decrease in GFR?
- Renal failure
- decrease in Cr urea excretion
- increase plasma creatinine
- increase BUN
- BUN / PCr (10-1 - 20/1)
What is the renal physiologic response to a hypovolemic state?
- Hypovolemic
- sympathetic stimulation and angiotensin II
- decreases GFR and decreases Cr excretion
- increase PCr and increase BUN
- increases reabsorption Na+, solutes, and water in the proximal tubule
- further enhances urea reabsorption secondary to the development of a favorable concentration gradient (increase BUN)
- THUS – increases BUN/PCr ration >20/1
- referred to as prerenal azotemia
- sympathetic stimulation and angiotensin II
How can you differentiate between Renal Failure & Prerenal Azotemia?
decrease GFR
- Renal Failure
- both BUN and PCr increase
- BUN / PCr remains normal (10/1 - 20/1)
- Prerenal Azotemia
- both BUN & PCr increase
- BUT, the BUN / PCR increase to >20/1
What types of acid are generated by daily metabolism?
How does the body maintain acid-base balance?
- Volatile (CO2) and non-volatile (50-150 mEq / day)
- The lungs “blow-off” CO2 getting rid of the volatile acid
- To maintain acid-base balance, the kidneys
- must excrete an amout of H+ equat to the daily production of nonvolatile (fixed) acids
- must prevent the loss of HCO3- in the urine, while replacing HCO3- that is lost in the buffering process
How is H+ secreted?
What enzye is responsible for producing a source of H+? What is this equation?
What other components are required for successful H+ secretion?
- An active process that moves H+ across the luminal membran into the tubule
- Carbonic anhydrase
- Requires:
- a H+ transporter (Na+ / H+ exchanger)
- proton acceptors in the tubular fluid
Describe what H+ does int eh proximal tubule.
- Na+- H+ exchanger
- Na+ is coming down its concentration gradient in exchange for protons
- Na+- HCO3
- bicarbonate generated by carbonic anhydrase is being reabsorbed
- Carbonic anhydrase
- in cell
- in lumen brush border
Describe what H+ does in the intercalated cells
- H+- ATPase
- proton pump (into lumen)
- H+- K+ ATPase
- Hydrogens to lumen & potassium in
- HCO3- reabsorption
- Carbonic anhydrase
- for every proton that gets pumped out, a bicarbonate is reabsorbed
- lumen (-) potential
What is the major source of H+?
- derived from the dissociation of H2CO3
- requires the enzyme carbonic anhydrase (CA)
What is the general shape of this graph?
What is normal PaCO2?
What is the minimum pH?
What can happen if it decreases below this minimum?
How do we continue to secrete H+ without reaching this minimum?
- Minimum: pH 4.5 (32 microM [H+])
- if [H+] is greater than this, H+ can leak out of the tubule & inhibit the proton pump
- Continued secretion of H+ requires proton pump acceptors in the tubular fluid
- actuall excrete ~100,000 microM H+/day
What are the three primary tubular H+ acceptors?
-
Bicarbonate (HCO3- –> CO2 + H2O)
- reabsorb CO2 & water and go back into the cycle
- Phosphate (HPO42-–> H2PO4-)
- because the phosphate, even when protonated, is charged, it gets diffusion trapped
- Ammonia (NH3–> NH4+)
What percent of bicarbonate is reabsorbed in the proximal tubule?
How does this happen?
- 90% filtered load of HCO3-
- H++ HCO3- = H2CO3= H2O + CO2 (volatile)
- reabsorption is coupled to Na+ reabsorption via H+ secretion
- Na+ enters the cell down its concentration gradient
- one H+ is secreted
- one HCO3- “disappears” from the tubular filtrate
- one HCO3- is produced int he cell and reabsorbed
- Excrete basicaly no bicarbonate, & have relatively acidic urine
Why is the “tubular transport maximum” of bicarbonate not a true one?
What is it actually a measure of?
- Not a true “transport maximum” b/c there is not carrier
- really a measure of hte capacity to secrete H+
- Normal plasma HCO3- is just slightly below the “renal threshold”
How much acid is produced in the body a day?
How do we excrete this much acid?
50-100 mEq acid / day
becasue this acid load is in excess of the H+ so it must be excreted as titratalbe acid adn ammonium (NH4+) & plasma bicarbonate levels must be restored
What is the principle titratable acid?
How does this lead to excretion of H+?
- Phosphate (HPO42-) is the principle titratable acid
- For each H+ that is secreted
- H+ titrates HPO42- to H2PO4- and is diffusion trapped and excreted
- one “new bicarbonate” is reabsorbed
What is the pKa of phosphate?
How does this impact its ability to act as a titratable acid?
- pKa is 6.8 - limited buffering capacity
- phosphate is largely used up before bare minimum urin pH (~4.5) can be achieved … so,
- other bases with lower pKa can accept protons
If the pKas of other bases are more suited to being buffers around pH 4.5, why are they not the prinicple titratable acids?
- they are only present in small amounts or not at al
- some have pKa values that are unfavorable for protonation within the normal range of urinary pH
What is the second most abundant buffer in the urine (after HCO3)?
NH3
How is NH3 synthesized?
Its synthesis is upregulated under what conditions?
How is it secreted?
- NH3 is synthesized in tubular cells from glutamine
- glutamine –> (glutaminase) –> NH3 + glutamate
- glutamate —> (glutamate dehydrogenas) –> NH3 + alpha-ketoglutarate2-
- NH3 production is up-regulated in acidosis
- Secreted as NH3 (or NH4+) by all segments of the nephron
- NH3 islipid soluble adn is secreted by passive diffusion
- Because NH4+ is charged, it is “diffusion trapped” and excreted
Describe the excretion of NH4+
- pKa for NH3 + H+ –> NH4+
- for each H+ that is secreted:
- one NH4+ is diffusion trapped and excreted
- one “new bicarbonate” is formed and reabsorbed
How can you determine the the amount of new HCO3- produced?
This is equal to what other value?
- The amount of H+ secreted beyond that needed ot reabsorb all the HCO3- is equal to the…
- the sum of the titratable acid and NH4+ in the urine
- For each titratable acid and NH4+ formed, one “new HCO3-” is formed and reabsorbed to restore the HCO3- levels in the plasma and body fluids
- New HCO3- production = Titratable acid + NH4+
- The amount of H+ secreted beyone that needed to reabsorb all the HCO3- is equal to the new HCO3-
How can you calculate the total H+ secreted?
the amount of H+ that was secreted to reabsorb the entire filtered load of HCO3- and to form the amount of titratable acid & NH4+ in the urine
What are they typical values for the indicated substances?
What factors influence the rate and extent of H+ secretion?
- the availability of urinary bases (H+ acceptors)
- Changes in arterial PCO2
- Aldosterone excess or deficit
- Hyperkalemia (K+- H+ exchange)
- and secondarily aldosterone
- Increased delivery of Na+ to the distal nephron
- eg. overuse of loop or thiazide diuretics; increases H+ secretion
