Spring 2009 Renal Physiology
Questions and Answers
I. David Weiner, M.D.
Professor of Medicine and Physiology
University of Florida and NF/SGVHS
If you have a question, please e-mail it to me at
David.Weiner@medicine.ufl.edu.
I'll post questions (without any identifying information as to
who submitted the question) and my answers as they come in.
In general, I will post questions and answers in reverse
order (most recent, first), so that you only have to read the most recent
questions and answers to stay up-to-date for new questions that have been posed.
April 17, 2009
Dear Dr. Weiner,
I had one more question, which I am afraid is a bit more mundane than the
first one:
For some reason, the notes I wrote during your acid-base lecture disagree
with my text in terms of A-type and B-type intercalated cell characteristics, so
can you please confirm if the following is correct:
The alpha-intercalated, or A-type, cells in the collecting duct secrete acid
using apical H+-K+-ATPase and H+-ATPase (identical to those in the beta cell,
and responsive to aldosterone).
The beta-intercalated, or B-type, cells in the collecting duct secrete
bicarbonate using the apical HCO3-Cl exchanger (Pendrin, which is distinct from
AE1 in the basolateral membrane of the A-type cell).
Many thanks,
I. David Weiner, M.D.
April 17, 2009
Hello Dr. Weiner, I had a few physiology questions:
1. Do the loop diuretics and thiazide diuretics have the same effects? Both
cause an increase in Na+ in the lumen which would immediately cause decrease in
Ca2+ reabsorption, and also cause K+ excretion in the Collecting Duct. But also,
do they both cause the proximal tubule to reabsorb Na+ and Ca2+ in the
long-term? If this is the case, then why doesn't Gittelman's syndrome cause a
Ca2+ excretion similar to that of Bartter's syndrome?
- No, they have very different effects. Loop diuretics increase calcium
excretion because they decrease TAL calcium reabsorption. Thiazide diuretics
cause decreased intravascular volume, which results in reflex stimulation of
Na+ absorption in the proximal tubule and the TAL, which increases calcium
absorption in these segments. This results in net decrease in calcium
excretion. Although loop diuretics can result in reflex increase in proximal
tubule calcium absorption their net effect, in most cases, is to increase
calcium excretion because the effect in the TAL is greater.
2. Does Aldosterone work to increase Na+ reabsorption and K+ excretion and
also stimulate the Na+/K+ ATPase pump?
- Yes, it does all three of the things you mentioned.
3. Are the 3 main regulators of K+ excretion: Aldosterone, prostaglandins and
increase Na+ delivery to the Collecting Duct?
- Those are three of the most important regulators.
4. In our notes, you mentioned that half of Ca2+ is bound to protein and this
is important when interpreting Ca2+ levels. You made an example of a patient
with total Ca2+ levels = 10 and Albumin levels = 2. This meant that the amount
of Ca2+ bound to protein is low. Could you explain this?
- You've described it perfectly. If the albumin is low, then calcium bound
to albumin is low. If, for example, total calcium, which is what the lab
measures, is normal, then the ionized (unbound) calcium must be high, in
this example. Since the ionized calcium is the biologically active calcium,
the patient is exposed to high calcium even though the total calcium is
normal.
5. Why does blocking the Anion exchanger 1 cause a distal tubule acidosis?
Would this also cause a metabolic acidosis?
- If you block AE1 then bicarbonate builds up inside the cell, which
decreases the H+ concentration, which decreases the intercalated cell's
ability to secrete H+ and reabsorb luminal bicarbonate. Yes, blocking it
will cause metabolic acidosis.
6. How does hypokalemia and hyperkalemia affect synthesis of ammonia?
- The exact mechanism by which alterations in extracellular potassium
alter proximal tubule ammonia production are unknown.
7. Why is there a metabolic alkalosis formed in both Gitterman's and
Bartter's syndrome?
- Intravascular volume depletion resulting from defective sodium
reabsorption leads to low BP, which stimulates aldosterone production. The
potassium losses and hypokalemia also stimulate ammonia metabolism. The two
together result in metabolic alkalosis.
Thank you for your time in answering so many questions!
I. David Weiner, M.D.
April 17, 2009
Dr. Weiner
I was wondering if you expect us to know the disease names that
you introduced to us this morning or if you would rather us just be familiar
with the effects of certain renal disturbances on reabsorption, etc. For
example, do you want us to know what Gittleman's syndrome is or would you rather
us know what a defect in the DCT reabsorption would cause?
Thanks
I. David Weiner, M.D.
April 17, 2009
Dr. Weiner,
Why does hypocalcemia cause seizures? In neuro, we learned that
it is an epic stimulation of neurons across the brain that causes seizures.
Since vesiclular release containing NT's is triggered by Ca2+ influx, how does
this mechanism work? I'm guessing there is an alternative pathway, perhaps
involving muscles?
- Good question. I don’t know.
Sorry.
I. David Weiner, M.D.
April 16, 2009
Hi Dr. Weiner,
I have a, more than likely, trivial question about prostaglandins and their
effect on K secretion. From Dr. Baylis lectures and yours, I learned that
prostaglandins act at the TAL of the loop of Henle and the collecting duct to
decrease Na reabsorptin in response to volume expansion. A drop in Na
reabsorption correlates to drop in K excretion. So, patients could become
hyperkalemic. Right?
From your lecture (and I may have interpretted this incorrectly) I wrote down
that NSAIDs that block the formation of prostaglandins can lead to hyperkalemia.
I'm confused.
Thank you for your help and patience.
-
Blocking prostaglandin production can lead to hyperkalemia.
Prostaglandins regulate the transport of the collecting duct principal cell
apical K channel. Decreasing prostaglandin production decreases the
transport capacity, decreasing the ability to secrete K, and leading to
hyperkalemia.
I. David Weiner, M.D.
April 16, 2009
Hi Dr. Weiner,
You mentioned briefly in the review today that ammonia acts as a weak
diuretic. Could you please explain how?
I. David Weiner, M.D.
April 15, 2009
Does Diamox block the Na/H exchanger??
I. David Weiner, M.D.
April 15, 2009
Hi Dr. Weiner-
What do you want us to know about Malox?
Thanks,
I. David Weiner, M.D.
April 15, 2009
Hello Dr. Weiner this --- ---- (1st year Med), I have been
getting into the Renal Path questions in BRS and I am having some trouble
keeping track of Potassium. For instance the text (Boron) as a general rule says
Alkalemia = Hypokalemia, but in the case of Ketoacidosis i read that you
actually become hypokalemic and with RTA 1 and 2, the same is true for the
reasons you gave in class.
Is this the difference between an Acute and Chronic disorder or
am I missing something. Thanks for your time.
- The text is correct in that most cases of alkalemia are associated with
hypokalemia. The key here is the word, "most." This generally occurs either
because the hypokalemia is actually part of the causation of the alkalemia
or because the renal response to the alkalosis, increasing renal bicarbonate
excretion, necessitates excretion of a cation (that balances the charge of
the bicarbonate). As we discussed in class, potassium comprises a major
component of the cations that balance the negative charge of bicarbonate.
Diabetic ketoacidosis can be associated with both hyperkalemia and
hypokalemia, and the potassium can change during the course of the disease.
Initially, DKA is typically associated with hyperkalemia. This is due to
both the insulin lack, which decrease cellular potassium uptake, and to the
hyperosmolality due to the hyperglycemia, which causes potassium to shift
from the intracellular to the extracellular fluid compartment. As the
disease continues, the potassium can either normalize or may even become
low. This is because the ketoacids are being excreted in the urine. They are
anions, and so they have to be balanced in charge by cations, again, mostly
potassium. Also, the hyperglycemia causes an osmotic diuresis by exceeding
the proximal tubule's capacity for glucose reabsorption, and the osmotic
diuresis increases renal potassium excretion. Thus, continued urinary
potassium losses can cause the disease to change from hyperkalemia to
hypokalemia.
When insulin is give to the patient with DKA the insulin can, in addition
to stimulating glucose uptake, stimulate potassium uptake. As a result the
serum potassium can decrease rapidly. Frequent measurements of the serum
potassium are necessary during the treatment phase of DKA.
I hope this helps.
I. David Weiner, M.D.
April 13, 2009
Dr. Weiner,
Your notes say that thiazide diuretics indirectly cause calcium and sodium to
be reabsorbed in the proximal tubule, so plasma calcium goes up. However, with
loop diuretics, the sodium cloride channel is blocked and so calcium excretion
is the major effect. But aren't these just blocking the solutes at different
points in the tubule? Why does the thiazide diuretics have an affect on the
proximal tubule but the loops diuretics don't? The only thing that makes sense
to me is that the blockage of both the Na/K/2CL and the Na/Cl channels cause a
backup and subsequent reabsorption in the proximal tubule. Would you be able to
clear this up for me?
Thank you,
-
The major difference between effects of thiazide diuretics
and loop diuretics is that loop diuretics block calcium absorption in the
thick ascending limb of the loop of Henle, whereas thiazide diuretics do not
have a direct effect on distal convoluted tubule calcium absorption.
Both loop and thiazide diuretics, by causing intravascular volume depletion,
can increase proximal tubule calcium reabsorption.
The major difference between the two on renal calcium metabolism is that
loop diuretics decrease thick ascending limb of the loop of Henle calcium
reabsorption whereas thiazide diuretics increase it.
Thus, the predominant effect of the loop diuretics is to decrease loop of
Henle calcium reabsorption and increase renal calcium excretion. However,
you are correct that under some circumstances that loop diuretics can
decrease calcium excretion. If the person becomes "too volume depleted,"
then there can be such stimulation of sodium absorption in the proximal
tubule with subsequent increase in proximal tubule calcium absorption, that
the net effect is decreased net renal calcium excretion.
I. David Weiner, M.D.
April 13, 2009
Hi Dr Weiner, why can urine sometimes maintain a positive voltage, and
sometimes a negative voltage, and not have these two voltages cancel each other
out?
thanks
-
The voltage to which you are referring is the difference in
electrical potential between the luminal fluid and the peritubular space.
This is generated by very slight differences in the cation and anion
concentrations in these two spaces. Although it is easy to think of
the luminal fluid as being an "electrically intact" conduit with free flow
of charge through the tubule lumen, the peritubular space is not.
Accordingly, this enables separate transepithelial voltages in different
portions of the renal nephron and collecting duct.
I. David Weiner, M.D.
April 13, 2009
Hi Dr. Weiner-
I am trying to figure out why there is a positive charge in the lumen of the
PT.
Is it because of the H ions that are pumped into the tubule? On the handout
about Ca/PO4 secretion it says that there is a + charge in the lumen b/c of
something to do with chloride????
A bit confused, please help!
Thanks,
- Sodium absorption in the proximal tubule involves sodium transport in
conjunction with other molecules (and occasionally counter transport) that
almost always results in net neutral charge movement. As a result, sodium's
movement does not result in a negative charge in the lumen.
The positive charge, that is actually present, does result predominantly
from paracellular chloride reabsorption.
The sodium, water and bicarbonate reabsorption that occurs in the
proximal tubule results in a relative concentration of the remaining
chloride in the remaining luminal fluid. This increase the intra-luminal
chloride concentration. Chloride is then able to move down its concentration
gradient though a paracellular pathway into the peritubular space. This
process involves movement of net charge, chloride's negative charge. As
result, this results in generation of a slight positive charge in the tubule
lumen relative to the peritubular space.
I. David Weiner, M.D.
April 13, 2009
Hi Dr.
I have some questions about aldosterone.
Aldosterone increases the activity of ENaC and the Na/K ATPase- therefore it
would increase K excretion
You also said that aldosterone increases the activity of the apical K/H
ATPase- this would increase K reabsorbtion.
So what is the overall affect of aldosterone - increased K excretion or
reabsorbtion???
Thanks,
- Excellent question. In almost all occasions, aldosterone's net effect
above on principal cell-mediated potassium secretion is greater than its
effect on H-K-ATPase-mediated potassium reabsorption. Accordingly,
aldosterone typically results in increased renal potassium excretion.
I. David Weiner, M.D.
April 12, 2009
Dear Dr. Weiner,
I am a first year medical student taking physiology and have a question about
the phosphate lecture.
You mentioned in your notes that protection against high phosphate levels
will prevent thrombosis, etc. I understand that you need to decrease calcitriol
in order to prevent gut absorption of phosphate. However, I would like
clarification on PTH levels.
I was under the impression that in order to decrease calcitriol to prevent
phosphate reabsorption you would also want to decrease PTH. However, an increase
in PTH prevents phosphate reabsorption in the proximal tubule. Do PTH levels
need to increase or decrease in order to alleviate hyperphosphatemia? (which one
wins?)
Thank you,
- PTH levels increase in order to alleviate hyperphosphatemia.
You are correct that increased PTH will increase calcitriol production,
which will increase gut phosphate absorption. However, PTH's effect on
proximal tubule phosphate reabsorption is much greater, thereby resulting in
next increases in phosphate excretion.'
Why, telologically, does PTH increase gut phosphate absorption? I don't
know. The interaction of PTH-calcitriol-calcium makes excellent sense as a
way to maintain calcium normal, and the calcitriol-PTH-phosphate interaction
makes perfect sense, but only as long as one "ignores" changes in gut
phosphate absorption.
Very good question - no way to know this logically!
I. David Weiner, M.D.
April 12, 2009
Dear Dr. Weiner,
I had a couple of questions regarding your renal physiology lectures:
1) Is extracelluar potassium a negative feedback mechanism to control insulin
activity? I have never seen it formally characterized this way, but based on
your lectures, one would expect a rise in insulin levels to cause a decrease in
ECF potassium levels, which would then reduce insulin's effect.
2) I have read that intense, prolonged exercise can cause transient
hyperkalemia, but without deleterious effects. Is this the evolutionary reason
why increased sympathetic tone activates the Na-K-ATPase (i.e., sympathetic
activation typically coincides with or precedes an intense burst of exercise,
thereby preparing the Na-K-ATPase to return K to the ICF more quickly)?
Many thanks,
- Very good questions!
I've never heard anyone talk about the teleologic benefit of the
potassium-insulin interaction. My thought is that it may reflect that
evolutionarily that the majority of carbohydrate ingestion came from fruits
and vegetables, which tend to be good sources of potassium. Thus the
glucose-stimulated insulin release might help in stimulating potassium
uptake, which would minimize the increases in extracellular potassium.
Yes, you are correct that exercise transiently increases extracellular
potassium, and your explanation provides a very good teleologic explanation.
The only catch is that didn't discuss that the SNS stimulates potassium
uptake through beta-adrenergic receptor stimulation, whereas
alpha-adrenergic stimulation decreases uptake. Thus, under most case where
there is balanced alpha- and beta-adrenergic stimulation there is minimal
change in potassium. Clinically, the biggest impact is when alpha- or
beta-adrenergic receptor specific inhibitors are used. In particular,
beta-adrenergic receptor antagonists blunt cellular potassium uptake,
leading to slight increases in serum potassium.
Love your thought process!
I. David Weiner, M.D.
April 12, 2009
Dr. Weiner, In the proximal tubule, what does the majority of Na
reabsorption, the Na/H exchanger or the Na/Glucose/Lactate,etc cotransporter?
Thanks
- Na-H exchanger, by a lot! Quantitatively there is less glucose,
phosphate, amino acids, etc. for cotransported mechanisms of sodium
reabsorption.
Sorry this wasn’t clear.
I. David Weiner, M.D.
April 10, 2009
Hi Dr Weiner, could you tell me what is the location in the nephron that 1,25
(OH)2D3 acts on?
The book said that PTH increases Ca2+ reabsorption in the thick ascending
limb, distal convoluted tubule, and connecting tubule and calcitonin stimulates
Ca2+ reabsorption in the thick ascending limb and distal convoluted tubule. Can
you confirm or correct these locations for me?
Also, I am having a hard time understanding why both PTH and Calcitonin
increase calcium reabsorption. Could you clarify that for me?
- It doesn't make sense to me, either.
I have been looking around in our notes and I have not found any hormones or
medications that act on the descending limb of the loop of Henle. Is that right?
- Correct. Essentially no active transport. AQP1 is present in the
descending thin limb and contributes to water reabsorption, but this process
does not have known hormones or medications that regulates it in this
segment.
I. David Weiner, M.D.
April 10, 2009
Dr. Weiner, I have a question regarding your lecture material. If you could
provide me with an explanations, that would be great and really appreciated.
Is there a lumen negative or positive charge at the proximal tubule area? I
thought there would be a negative, due to all of the Na leaving the tubular
fluid and going into the cells. In your notes you mention that there is a lumen
positive, due to paracellular chloride reabsorption. Will you explain this a bit
more? I can't find any information regarding that and its confusing me a bit.
-
Sodium absorption in the proximal tubule involves sodium
transport in conjunction with other molecules (and occasionally counter
transport) that almost always results in net neutral charge movement. As a
result, sodium's movement does not result in a negative charge in the lumen.
The positive charge, that is actually present, does result predominantly
from paracellular chloride reabsorption.
The sodium, water and bicarbonate reabsorption that occurs in the proximal
tubule results in a relative concentration of the remaining chloride in the
remaining luminal fluid. This increase the intra-luminal chloride
concentration. Chloride is then able to move down its concentration gradient
though a paracellular pathway into the peritubular space. This process
involves movement of net charge, chloride's negative charge. As result, this
results in generation of a slight positive charge in the tubule lumen
relative to the peritubular space.
I hope this helps.
I. David Weiner, M.D.
April 10, 2009
Hi Dr. Weiner,
In my notes from yesterday's lecture on calcium and phosphate homeostasis I
noticed that I had draw the proximal tubule sodium-phosphate transporter as
moving PO4 2- ions but in your notes in the packet it is inorganic phosphate
that is being reabsorbed. Is it both or did I write something down incorrectly?
Thank you for the clarification.
I. David Weiner, M.D.
April 10, 2009
Dr. Weiner,
In your lecture on K+, you state that NSAIDs will decrease
Prostaglandins, which, in effect, cause Hyperkalemia. Why?
-
Prostaglandins are important for regulating the transport
activity (open probability) of the apical potassium channels present in
collecting duct principal cells that secrete potassium. When you block
prostaglandin production, these channels "close," thereby decreasing the
collecting duct's ability to secrete potassium. Ergo, hyperkalemia can
develop.
I hope this helps.
I. David Weiner, M.D.
April 10, 2009
Dr. Weiner, I know it was asked yesterday in lecture, but I
don't think you ever covered it. Why do high levels of K+ cause hypertension?
Sorry, let me amend that: why do low levels of K+ cause hypertension?
First, it causes NaCl retention and intravascular
volume expansion. In part, this is because the H-K-ATPase in the collecting
duct intercalated cell can bind and transport sodium at potassium-binding
site. Hypokalemia, to no great surprise, causes increased expression of
H-K-ATPase, probably in a teleological attempt to maximize potassium
reabsorption. Because of the increased expression of H-K-ATPase and the
relative lack potassium for binding to the potassium-binding site, there is
increased reabsorption of sodium by H-K-ATPase. This then leads to
intravascular volume expansion and contributes to the hypertension.
Second, hypokalemia results in increased reactive
oxygen species generation. This leads to increased vasoconstriction of
vascular tissues. This is a second mechanism contributing to hypertension.
Finally, hypokalemia causes an intrarenal arterial
disease, leading to the kidney sensing decreased perfusion pressure and
activating mechanisms that result in increased generation of hypertension by
the kidneys.
I. David Weiner, M.D.
April 8, 2009
Hey Dr. Weiner,
I remember when my sister was in high school that she would get serious leg
cramps while playing basketball for an extended period of time. The remedy of
her coach as well as my mom was always to have a banana on hand which seemed to
do the trick almost every time. I was wondering if you could explain how K+ is
used to alleviate the hyperactive firing of action potentials if it actually has
the effect of increasing (making more positive) the membrane potential, making
an AP more attainable. I may be looking at this wrong, but it seems
counter-intuitive based on what we discussed today in class.
Thanks so much! --
- The problem with muscle cramps is that why they occur is very poorly
understood. Changes in serum potassium, I believe, are very unlikely to play
a critical factor in their etiology. In particular, serum potassium levels
actually increase during exercise due to release from exercising skeletal
muscle cells. Thus, it is hard for me to understand what beneficial effect a
further increase in serum K would have.
- The improvement in her symptoms may have been related to resting,
decreased sympathetic nerve stimulation (possibly partially assisted by
reassurance that she was doing something, eating bananas, that would help
the cramps), other nutrients in the bananas, or ?
- Sorry I can't tell you the definitive mechanism.
I. David Weiner, M.D.
April 6, 2008
Dr. Weiner, I was going over the rest of the lecture on the
pharmacology of Na+ excretion, and I was wondering what happens to the Na/KATPase
when you inhibit apical transport proteins? Does the cell just reach a certain
base negative charge, similar to a neuron's normal state, where the Na/K pump is
no longer effectively working? Does this affect the epithelial cells lining the
tubules/ducts? Or does something else happen?
Thanks,
-
One of the major regulators of Na-K-ATPase transport rate is
intracellular sodium. When you inhibit apical sodium entry continued
basolateral Na-K-ATPase activity will result in lowering of intracellular
sodium, and this will feedback to inhibit Na-K-ATPase-mediated sodium
extrusion. Eventually, sodium extrusion rates decrease sufficiently
that it equals sodium entry rates.
-
There are also other sodium transporters in cells that serve
other functions, such as sodium-calcium exchangers and sodium-linked
bicarbonate transporters. Thus, even with complete inhibition of
apical sodium entry there will still be residual sodium entry via these
other mechanisms. It will just be relatively slower. This is why
essentially all cells need an Na-K-ATPase.
I. David Weiner, M.D.
April 6, 2008
Dr. Weiner,
There are only 2 places in the kindey tubule system that
do not actively transport sodium (the thin ascending and thin descending loop of
henle). Do these 2 places still have a basolateral Na/K ATPase?
-
Yes, they do. Essentially all cells in the
body, with the possible exception of erythrocytes, have Na-K-ATPase.
This protein is needed to maintain normal, that is low, intracellular sodium
and, normal, that is high, intracellular potassium. The latter is
needed to maintain intracellular electronegativity, which is critical for
regulation and maintenance of intracellular calcium.
I. David Weiner, M.D.
April 6, 2008
Hi Dr Weiner, it is written on your lecture that potassium is pumped in
towards the DCT cell at the peritubular side, via the Na/K pump what happens to
potassium on the urine side of the DCT cell, to avoid having an infinite charge
imbalance?
thanks
I. David Weiner, M.D. |
