Pulmonary Physiology Week 0.5 Flashcards
Describe the types of acids the body must deal with to maintain a mildly alkaline pH.
Large load of volatile acid (CO2–> carbonic acid) and a much smaller, more difficult load of non-volatile acid (H2SO4 from protein)
What is the normal pH of the body?
7.4
_______ the first line of defense against an acid load
Chemical buffering
______ is the second line of defense against an acid load
Regulation of CO2 levels by the lungs
_______ is the third line of defense against an acid load
Regulation of fixed (metabolic) acid and bicarbonate by the kidneys
Describe the four ways in which kidneys maintain physiological pH
1) conserve filtered bicarb; 2) make new bicarb to replace lost bicarb; 3) excrete xs bicarbonate in alkalosis; 4) excrete fixed acid
How do the kidneys excrete fixed acid?
Turn carbonic acid into new bicarb (which is reabsorbed) and H+ (which is excreted).
Where does the majority of bicarbonate reabsorption occur? (when pH is less than 6)
80% occurs in the proximal convoluted tubule
In what areas is bicarbonate reabsorbed? (when pH is less than 6)
15% in the thick ascending limb of LOH and 5% in the cortical collecting duct/distal tubules
[according to guyton-hall - all parts except for thin limbs of LOH]
For each bicarbonate reabsorbed, what must be secreted?
One H+!!!!!!
Describe the process by which CO2 drives bicarbonate reabsorption in the proximal tubules.
CO2 either diffuses into tubular cell or is created within the tubular cell then joins with H2O to form carbonic acid [reaction driven by carbonic anhydrase]. Carbonic acid then dissociates into bicarbonate and H+. Bicarbonate is reabsorbed into interstitial fluid whereas H+ is secreted into the the tubular lumen via Na/H antiporter
Describe the process by which bicarbonate is reabsorbed from the lumen.
The lumen is not permeable to bicarbonate, therefore bicarbonate joins with secreted H+ to form carbonic acid in the lumen. The carbonic acid then dissociates to form CO2 and H2O. CO2 diffuses into the tubular cell then recombines with H2O to form new carbonic acid –> new bicarb –> reabsorbed into interstitial fluid
Whenever an H+ is formed in the tubular epithelial cells, what happens?
An HCO3- is formed and released back into the blood! Reabsorption of bicarb yay!
Does reabsorption of bicarbonate from the tubular lumen result in net secretion of H+?
No, because the H+ that is secreted is used to form carbonic acid then CO2 and H2O and blah blah blah
What are the two types of epithelial cells located in the distal nephron/collecting duct? Which secrete acid?
Principal cells (65%) and alpha-intercalated cells (35%). Alpha-intercalated cells secrete acid.
Why is bicarbonate reabsorption an ATP driven process?
tubule can be highly acidic on inside (down to 4.4) so need energy so secrete H+ ions into lumen.
How is energy for H+ secretion into tubular lumen derived in the proximal tubule, LOH, and early distal tubule?
The Na/K ATpase on the basolateral membrane establishes a Na+ gradient [Na+ reabsorbed into interstitial space]. This provides the energy for the Na/H antiport on the apical membrane [facing the tubular lumen], so Na+ reabsorbed and H+ secreted into lumen
What are the two major differences in bicarbonate reabsorption in the intercalated cells of the late distal tubule/CCT in comparison to other areas of the nephron?
1) H+ is secreted into lumen via ATP-driven transporter [in other parts, via Na+/H+ secondary active transport]
2) Carbonic anhydrase is not found on the apical membrane of alpha-intercalated cells
What happens to bicarbonate in an alkalotic patient?
In an alkalotic patient, increased bicarbonate in the lumen leads to increased excretion of bicarbonate and increased urine pH. All of the H+ is used up, so only a maximal amount of carbonic acid can be formed to recycle into tubular cells and back into body, so remaining HCO3- is excreted.
What is the function of carbonic anhydrase?
Carbonic anhydrase drives the formation of carbonic acid from H2O and CO2.
Why are carbonic anhydrase inhibitors such as Diamox used?
To relieve alkalosis quickly such in the case of mountain sickness. Prevent bicarbonate reabsorption from the kidney by preventing the formation of carbonic acid, an intermediary step in the process. Therefore, more bicarbonate is excreted and pH returns to normal.
Why does mountain sickness cause alkalosis?
When you are at a high elevation, there is a decrease in PO2 so you breathe more rapidly, therefore expire more CO2, which leads to respiratory alkalosis
What is a problematic side effect of carbonic anhydrase inhibitors such as Diamox?
Bicarbonate excretion also boosts Na+ excretion which leads to osmotic diuresis and then dehydration.
How does bicarbonate excretion (decrease in absorption) such as seen in carbonic anhydrase inhibitors boost Na+ excretion?
Na+ is normally reabsorbed from the lumen via the Na+/H+ antiport in the proximal tubule. However, if a carbonic anhydrase inhibitor used, then less CO2 enters tubule cells, so less bicarbonate and H+ are made, so the H+ antiporter does not uptake much Na+.
What are the two ways by which the kidney eliminates fixed acid?
1) formation of titrateable acid; 2) formation of ammonium (NH4+)
_________ is the predominate titrateable acid in tubular fluid
Phosphate (PO4 3-)
Describe the titration curve of phosphate.
If pH decreases, phosphate will pick up H+ and make H2PO4-. As pH increases, phosphate will pick lose H+ and will have HPO4 2-.
In normal body pH, which form of phosphate is more common?
HPO4 2-
Describe the formation of titrateable acid in the lumen.
After the transport maximum for phosphate is reached, the phosphate that remains in the lumen combines with excess H+ to form H2PO4-. This stabilizes the pH in the urine and then H2PO4- is excreted as a sodium salt.
How is excretion of large amounts of H+ in the urine accomplished (2 molecules)?
via phosphate and ammonium buffers
Whenever an H+ secreted in the tubular lumen combines with a buffer other than bicarbonate, where is there a net gain?
Net gain in bicarbonate. In the tubular cell, bicarbonate and H+ are formed together. Since the H+ formed is being excreted, there is a net gain of bicarbonate returning to body (no longer a replacement)
Why is most buffering done via the ammonium system rather than the phosphate system?
Under normal conditions, most phosphate is reabsorbed, so only limited quantity available for buffering
Glutamine is transported into the proximal tubular cells where it is metabolized to form what two molecules?
2 NH4+ (ammonium) and 2 HCO3- (bicarbonate)
What happens to the ammonium and bicarbonate that is formed from glutamine metabolism in the proximal tubule?
Ammonium is secreted into the tubular lumen via antiport with sodium (sodium reabs). The bicarbonate is then reabsorbed into interstitial fluid(back to body) with the Na+.
Basically, for each molecule of glutamine metabolized in the proximal tubules, two NH4+ molecules are ______ and two HCO3- molecules are ______.
secreted into the urine, reabsorbed into this blood.
How does the ammonium buffering system work in the collecting tubules?
H+ is secreted via ATPase on apical membrane of tubular cell. The H+ combines with NH3 to form NH4. The tubular cell membrane is permeable to NH3 but not NH4+ therefore NH4+ is trapped and is excreted. As usual, for each H+ secreted, there is an HCO3- reabsorbed.
True/False: The ammonium buffering system in the collecting tubules generates new bicarbonate.
FALSE - generates new bicarbonate in the proximal tubules.
Describe the mechanism of action of aldosterone in principal cells in distal tubule/collecting duct
Stimulates Na+ reabsorption and K+ secretion in the principal cells of the collecting duct
Describe the mechanism of action of aldosterone in alpha intercalated cells in distal tubule/collecting duct
Stimulates H+ secretion [and indirectly bicarbonate reabsorption]
What is the biggest job the kidneys perform?
Reabsorption of filtered bicarbonate
How do you calculate the reabsorption rate of bicarbonate?
It is equal to the amount filtered minus the amount excreted (F-E). At urine with pH=6, the amount excreted is negligible.
What is the formula for net acid excretion (NAE)?
TA (titrateable acid) + NH4+ - HCO3 in urine
[TA + NH4 equal H+ excretion]
What is the net acid excretion equal to?
Amount of new bicarbonate (HCO3-) generated
Per day, about ___ mmol of HCO3- is excreted whereas ____ mmol of HCO3- is added back to the body (in a normal state). In comparison, ___ mmol of titrateable acid and ___ mmol of NH4+ is excreted
1, 59, 20, 40
What occurs to the excretory values of titrateable acid, NH4+ and HCO3- in acidosis?
TA and NH4+ increase whereas no HCO3- is excreted [lots is reabsorbed]
What occurs to the excretory values of TA, NH4+ and HCO3- in alkalosis?
TA and NH4 are not excreted (0); HCO3- excretion is increased [none is reabsorbed].
True/False: New bicarbonate far exceeds reabsorbed bicarbonate
FALSE - reabsorbed exceeds new. About 4150 mmol/day reabs compared to 60 mmol/day made new.
True/False: H+ secretion is only required for reabsorbing HCO3-
FALSE - H+ secretion required for reabsorbing and making new HCO3-
True/False: The amount of H+ secreted far exceeds the amount of acid that is excreted
TRUE
How is fixed acid measured in the urine?
Add OH- until pH returned to 7.4. The amount of OH- added tells you how much acid was in the urine.
How is NH4+ excretion measured in the urine?
by determining NH4+ content of urine (no brainer)
What happens to NH4+ concentration in diabetic ketoacidosis?
It increased by a 10X factor [TA also increases by 7-8X]
What happens to NH4+ concentration in chronic renal disease?
It decreases significantly due to nephrons dying (to 0.5 to 15 per day)
What are the normal mEQ of urinary H+ per day?
NH4+ is 30-50. TA is 10-30.
In K+ losing diuretics, how does the resultant hypokalemia leads to alkalosis?
Loop diuretics and thiazide are going to increase NaCl concentration in tubular lumen and thus flow. Greater flow is going to lead to a greater K+ concentration in lumen. Because of this, more K+ will be reabsorbed via the K+/H+ antiport in the tubular lumen. Thereby increasing H+ secretion and eventual excretion. In addition, H+ secretion is coupled with HCO3- reabsorption. Thus, alkalosis.
How does furesomide cause hypokalemia?
1) The increased urine flow means more K+ will get whisked away and have little chance for reabsorption; 2) greater Na+ delivery in the cortical collecting duct means more K+ is secreted
How do K+ sparing diuretics cause acidosis?
Na+ conductance on the apical membrane of the cortical collecting duct is blocked so membrane is hyperpolarized –> less K+ secreted into duct lumen –> less K+ is going to leave in the alpha intercalated cells –> less h+ secreted into lumen via K+/H+ antiport in alpha intercalated cells –> acidosis
K+ losing diuretics cause _____ whereas K+ sparing diuretics cause _____
alkalosis, acidosis
How does addition of inorganic acid to the tubular lumen lead to metabolic acidosis and subsequently hyperkalemia?
More H+ in tubular lumen means that H+ won’t flow in as easily via Na/H antiporter on apical membrane of tubular cell. This will diminish Na+ conductance into the tubular cell. Due to this, the Na+/K+ antiporter on the baso lateral membrane will have diminished activity. Therefore, K+ secretion will decrease. Overall, decreased secretion of H+ and K+ into the tubular lumen translates to metabolic acidosis and hyperkalemia.
How does diabetic ketoacidosis lead to metabolic acidosis?
In DKA, not sufficient insulin, so body starts breaking down fat for energy which leads to increased acetoacetic acid levels –> metabolic acidosis
How does lack of insulin in diabetic ketoacidosis lead to hyperkalemia?
Insulin normally stimulates the Na/K pump on the basolateral membrane. Since there is a lack of insulin, the Na/K pump is inhibited. K+ does not get secreted into tubular lumen which causes increased [K+]o
What happens to increased [K+}out in DKA?
Some of it is lost in urine which depletes the body stores of K+.
Why must one be careful when administering insulin to a patient in DKA?
Can lead to hypokalemia because Na/K starts working which is going to lead to more K+ being excreted from the cell
How does diarrhea lead to hypokalemia?
Diarrhea causes acidosis, which means that K+ shifts out of cells (since H+ shifts in to relieve acidosis). Since K+ is shifting out of cells, there are losses of K+ in both diarrhea and urine. More loss than cellular shift –> hypokalemia.
How does renal failure lead to hyperkalemia?
Loss of functioning nephrons inhibits K+ excretion.
How does renal tubular acidosis lead to hypokalemia?
Both cause urinary spillage of K+.
True/False: In DKA, hyperkalemia is due to H+/K+ shift.
FALSE, due to lack of insulin
What changes in [K} are caused by lactic acidosis?
None. Normal [K]o because no K+/H+ shift is promoted due to balanced accumulation on both sides.
Choose: progressive chronic renal disease causes metabolic acidosis/alkalosis and hypokalemia/hyperkalemia
Causes metabolic acidosis and hyperkalemia. Acidosis caused by diminished ability to eliminate fixed acid. Hyperkalemia caused by diminished ability to excrete K+ because less K+ filtered.
Type I renal tubular acidosis affects the ________ and is therefore referred to as ____ RTA
collecting duct, distal
Describe four abnormalities that would cause type I (distal) renal tubular acidosis
(1) impaired apical H+ ATPase; (2) impaired H+/K+ ATpase; (3) impaired HCO3-/Cl- exchanger; (4) increased apical membrane leakiness to H+
EITHER DEC HCO3- REABS OR DEC H+ SECRETION.
All will prevent establishment of H+ gradient and prevent H+ from entering lumen.
How would you test to see if someone has renal tubular acidosis?
Give individual ammonium chloride (NH4Cl) which will produce HCl in the liver. If person’s urine does not decrease pH below 5.5, person likely has renal tubular acidosis.
True/False: Renal tubular acidosis leads to excretion of acidotic urine.
FALSE - leads to excretion of alkalotic urine due to either decreased HCO3- reabsorption and/or decreased H+ secretion.
Choose: Renal tubular acidosis leads to hypokalemia/hyperkalemia and hypochloridemia/hyperchloridemia
hypokalemia, hyperchloridemia. Urine K+ increases because H+ secretion decreases [less K+ reabsorbed] leading to hypokalemia. [Per Keef, K+ follows bicarb]. Urine Cl- decreases because decreased bicarbonate reabsorption via bicarb/Cl- antiporter means that less Cl- is being secreted into the tubule.
Which of the following is not a possible consequence of Type I renal tubular acidosis?
a) bone demineralization
b) urinary stone formation
c) nephrocalcinosis (deposition of Ca++ in kidney)
d) failure to thrive
e) all of the above are consequences
F.
bone demineralization due to acidity.
Name 6 manifestations of RTA.
growth retardation, bone disease, intermittent muscle weakness (hypoK), kidney stones, progressive renal failure, death
Fanconi syndrome is a generalized disorder of __________ reabsorption
proximal tubule
Why does NH4Cl decrease urine pH below 5.5 in type II RTA but not type I?
Type II RTA affects the proximal tubule therefore a large gradient of H+ can still be generated in distal tubule to decrease concentration below 5.5.
What are the treatments for renal tubular acidosis?
Akali replacement (1-3 mmol/kg/day base) and sodium bicarbonate/sodium citrate; potassium citrate if hypokalemia is present
Describe the physiological response to a single episode of vomiting.
Loss of acid –> Body is left alkalotic –> kidneys secrete less H+ to compensate –> less titrateable acid and less bicarbonate reabsorbed. Less TA –> less new bicarbonate formed.
Overall, body dumps bicarb and brings pH back to normal.
Also, K+ follows HCO3- so increased HCO3- excretion would result in increased K+ excretion.
Describe the physiological response to multiple days of vomiting. [plasma Cl-, K+, HCO3-, Na, pCO2, BUN, Creatinine, urine pH, urine Na, urine K, and urine Cl-]
Multiple days of vomiting will lead to metabolic alkalosis. HCl- is lost per vomitus, so Cl- will decrease. Loss of volume with trigger increased reabsorption of Na+, so K+ will be excreted in greater amounts, leading to hypokalemia. Since arterial pH is alkalotic (increased HCO3-), person will decrease respiration so pCO2 will increase to decrease pH. BUN will be high due to decreased volume - then dec volume will lead to dec GFR which will amplify this. Creatinine will be high for similar reason. Urine will be acidic (body is prioritizing volume retention over acid/base balance to prevent cardiovascular collapse) and urine Na will be negligible because body reabsorbing everything it can. Urine K+ will be decreased due to resultant hypokalemia, and urine Cl- will be decreased due to loss of Hcl- through vomitus.
Why does an individual with metabolic alkalosis due to prolonged vomiting produce acidic urine?
Hypokalemia results from extensive reabsorption of Na+. Body will want to reabsorb potassum, which will drive H+ secretion into tubule leading to a decrease in urine pH.
Describe the effects of hyperaldosteronemia on 1) H+, 2) K+, 3) Na+
Aldosterone promotes Na+ reabsorption from distal and collecting tubule [ and therefore K+ secretion ] and also stimulates secretion of H+ by intercalated cells in collecting tubules. This leads to metabolic alkalosis.
Severe ______ can lead to flaccid paralysis of muscles of the lung leading to respiratory arrest and arrhythmias that can cause death from cardiac arrest
hypokalemia
________ can lead to frank muscle paralysis or shortness of breathe due to effects on muscular or cardiac function and asystolic cardiac arrest may develop after widened QRS complex and flattened P waves seen
Hyperkalemia
What is the effect of hyperosmolarity on plasma K+ concentration?
Hyperosmolarity leads to increased plasma K+ concentration because shifts K+ out of cells. This is because water shifts out of cells to balance osmolarity, which causes intracellular K+ concentration to rise, which creates a K+ gradient that favors K+ movement out of the cell.
What is the body’s compensatory mechanism for respiratory acidosis?
Respiratory acidosis caused by increased pCO2 which leads to compensation via increased HCO3- levels (metabolic)
What is the body’s compensatory mechanism for respiratory alkalosis?
Respiratory alkalosis is caused by decreased pCO2 which leads to compensation via decreased HCO3- levels (metabolic)
What is the body’s compensatory mechanism for metabolic acidosis?
Metabolic acidosis is caused by decrease in HCO3- levels which is compensated for by hyperventilation to drop PCO2 (respiratory)
What is the body’s compensatory mechanism for metabolic alkalosis?
Metabolic alkalosis is caused by increase in HCO3- levels which is compensated for by hypoventilation to increase PCO2 (respiratory)
How does Bartter syndrome/Furesomide lead to hypokalemia?
Bartter syndrome is caused by a mutation in Na/K/Cl transporter in thick ascending limb of LOH. Because of this, Na+ reabsorption in the distal tubules is increased, which means that K+ excretion is increased.
This increased K+ excretion is somewhat compensated by alpha-intercalated cells which sacrifices H+ ions leading to metabolic alkalosis.
How does Gittelman’s Syndrome/Thiazide lead to hypokalemia?
Gittelman’s syndrome is caused by mutation in Na/Cl transporter in distal tubule. Therefore, more Na+ reabsorption promoted later in the tubule means more K+ excretion –> hypokalemia
